Research Brochure

2014-2015 | Pathology Basic Scientific Research
Massachusetts General Hospital

Molecular Pathology Unit
149 13th Street, 6th Floor
Charlestown, MA 02129
Phone: 617-726-5690
Fax: 617-726-5684
http://www.massgeneral.org/pathology/researchpath/
Cover Photo:
Confocal microscopic image of a RAS-induced embryonal rhabdomyosarcoma (ERMS) arising in a fluorescent transgenic
zebrafish. Green fluorescent protein expression is confined to the myf5+ ERMS-propagating cells that drive continued tumor
growth and relapse. The nuclei of differentiated tumor cells are labeled with blue fluorescent protein and myosin antibody
(MF20, red). Large-scale chemical genetic approaches have now been developed to kill tumor cells in the zebrafish and to assess
drug effects on heterogeneity within the model. These approaches have identified novel therapeutic strategies that are now
moving toward clinical development.
TABLE OF CONTENTS
INTRODUCTION...............................................................................................................................ii
TRAINING GRANT LABORATORIES...............................................................................................iii
FACULTY

J. Keith Joung .................................................................................................................................1
David M. Langenau ........................................................................................................................2
Martin Aryee...................................................................................................................................3
Atul K. Bhan....................................................................................................................................4
A. John Iafrate ................................................................................................................................5
David N. Louis .................................................................................................................................6
Miguel Rivera .................................................................................................................................7
Dennis C. Sgroi ...............................................................................................................................8
Anat Stemmer-Rachamimov ..........................................................................................................9
Mario L. Suvà ................................................................................................................................10
Howard Hughes Medical Institute

Bradley Bernstein .........................................................................................................................11
Jeannie T. Lee (Molecular Biology) .............................................................................................12
Translational Oncology Laboratory

Dora Dias-Santagata ....................................................................................................................13
Long Phi Le....................................................................................................................................14
Experimental Pathology Unit

Frederic I. Preffer .........................................................................................................................15
James R. Stone ..............................................................................................................................16
Immunopathology Research Unit

Robert B. Colvin ...........................................................................................................................17
Rex Neal Smith .............................................................................................................................18
Pathology Imaging
Yukako Yagi ..................................................................................................................................19
Guillermo J. Tearney (Wellman Center for Photomedicine) .....................................................20
Pathology Faculty Affiliated With Other Departments

Matthew P. Frosch: MassGeneral Institute for Neurodegenerative Diseases..........................21
Gad A. Getz: Center for Cancer Research..................................................................................22
John M. Higgins: Center for Systems Biology............................................................................23
Andrea I. McClatchey: Center for Cancer Research...................................................................24
Eric S. Rosenberg: Infectious Diseases........................................................................................25
Chin Lee Wu: Urology-Pathology Research Laboratory............................................................26
Ömer H. Yilmaz: Koch Institute for Integrative Cancer Research at MIT.................................27
Lee Zou: Center for Cancer Research ........................................................................................28
MGH PATHOLOGY | i
INTRODUCTION
Pathology plays a key role in academic medicine, as a natural bridge between the study of human
disease and experimental biological investigation. Major advances in molecular pathology and in
pathology informatics are accelerating the pace of this translational research. In turn, the rapidity
and frequency of interactions between the clinical and scientific areas makes this a very exciting time
in the field of pathology.
Laboratory-based scientific research is a major component of MGH Pathology, and is complemented

by productive clinical research activities. As a result, MGH Pathology provides an exciting stage for basic
and translational research. The present brochure highlights the basic scientific research activities in
MGH Pathology.
Basic research at MGH Pathology, which is organized under the Division of Research, is divided
among a variety of laboratories, both within the Pathology Service and other MGH departments.
Peer-review funded investigators in MGH Pathology are centered in the Molecular Pathology Unit,
with additional departmental laboratories in the Howard Hughes Medical Institute, the Center for
Integrated Diagnostics, the Experimental Pathology Unit, the Pathology Imaging Laboratory, and the
Immunopathology Research Unit. In addition, many peer-review funded pathologists and members of the
Harvard Medical School Department of Pathology have laboratories in other MGH departments, including
the Cancer Center, the Infectious Disease Unit, Neurology, Urology and Wellman Photomedicine.
Basic research activities have been expanded greatly over the past ten years, including: creation of the
Division; recruitment of ten basic scientists at the Assistant Professor level and five at the Instructor level
(with eight as full members of the Center for Cancer Research, three as members of the Harvard-MIT
Broad Institute and five as members of the Harvard Medical School Biological and Biomedical Sciences
program); addition of five molecular diagnostic pathologists; acquisition of considerable additional
Pathology research space that has been extensively renovated; expansion in the number of Harvard
and MIT Ph.D.-candidate graduate students training in MGH Pathology laboratories; and provision of
competitive pilot grants to junior clinical faculty. As a result, the group has seen an extraordinary increase
in the amount of NIH funding.
In coordination with the growth of molecular pathology research, molecular diagnostic activities
have also expanded greatly, including: development of the MGH Center for Integrated Diagnostics
(led by A. John Iafrate); organization of the MGH Pathology component of the Harvard-wide Molecular
Genetic Pathology fellowship; extension and further development of the molecular pathology rotation
for Pathology residents; and extensive expansion of the CLIA-approved molecular diagnostics laboratory,
with implementation of a novel, high-throughput clinical mutation screening program through the
Translational Research Laboratory.
We are currently implementing initiatives identified from our recent departmental strategic planning
process. With support and resources from the department and the hospital, we are expanding
computational biology and bioinformatics resources for pathology, expanding collaborations and
interactions with the Center for Integrated Diagnostics, and building additional links between basic and
clinical/translational researchers within MGH Pathology. We also continue to recruit additional basic
science principal investigators and to develop new research space. These efforts will ensure that MGH
Pathology faculty remain at the forefronts of their fields, enabling them to continue advancing our
understanding and diagnosis of human diseases.
J. Keith Joung, MD, PhD

Associate Chief of Pathology (Research), Massachusetts General Hospital
Associate Professor of Pathology, Harvard Medical School
ii | MGH PATHOLOGY
MGH TRAINING GRANT LABORATORIES
MGH Pathology directs an NIH Training Grant that provides post-doctoral fellowship support for residents
wishing to pursue scientific training following their clinical years. MGH Pathology trainees have had
considerable success garnering individual grants for research fellowships. Our trainees have been authors
on well over 100 publications, in journals that include Cell, Science, Nature, Cancer Cell, Developmental
Cell, Molecular Cell, Nature Genetics, Nature Biotechnology, Nature Methods, Current Biology and PNAS.
Many trainees undertake post-doctoral fellowships in MGH Pathology laboratories. MGH Pathology
trainees have also done fellowships with other investigators, including the following over the past
20 years:
Nancy Andrews, MD, PhD James Fox, PhD Shiv Pillai, MD, PhD
Children’s Hospital Massachusetts Institute of MGH Center for Cancer Research
Technology
Spyros Artavanis-Tsakonas, PhD Sridhar Ramaswamy, MD
Harvard Medical School Frank Gertler, PhD MGH Center for Cancer Research
Massachusetts Institute of
David Bartel, PhD Technology David Sabatini, MD, PhD
Whitehead Institute Massachusetts Institute of
Daniel Haber, MD, PhD Technology
Alan Beggs, PhD MGH Center for Cancer Research
Children’s Hospital Neurology/ David Scadden, MD
Genetics Wenlei He, MD, PhD MGH Hematology-Oncology
MGH Department of Urology
Andre Bernards, PhD Emmett Schmidt, MD, PhD
MGH Center for Cancer Research Konrad Hochedlinger, PhD MGH Center for Cancer Research
MGH Center for Regenerative
Brett Bouma, PhD Medicine Jeffrey Settleman, PhD
MGH Wellman Center for MGH Center for Cancer Research
Photomedicine Bradley Hyman, MD, PhD
MGH Neurology Carla Shatz, PhD
Connie Cepko, PhD HMS Neurobiology
HMS Genetics Frank Haluska, MD, PhD
MGH Hematology-Oncology Melissa Suter, PhD
George Church, PhD MGH Wellman Center for
Harvard Medical School Ralph Isberg, PhD Photomedicine
Tufts University
Catherine Costello, PhD Jay Vacanti, MD, PhD
Boston University Rudolf Jaenisch, MD MGH Pediatric Surgery
Massachusetts Institute of
Michael Detmar, MD Technology Amy Wagers, PhD
MGH Cutaneous Biology Harvard Department of Stem
Research Center Rakesh Jain, PhD Cell Regenerative Biology
MGH Radiation Oncology
Iain Drummond, PhD Robert Weinberg, PhD
MGH Renal Unit Susan Lindquist, PhD Massachusetts Institute of
Massachusetts Institute of Technology
Kevin Eggan, PhD Technology
Harvard University Ramnik Xavier, MD, PhD
Carl Pabo, PhD MGH Gastrointestinal Unit
Stephen Elledge, PhD Massachusetts Institute of
Harvard-Partners Center for Technology Gary Yellen, PhD
Genetics and Genomics HMS Neurobiology
MGH PATHOLOGY | iii

MOLECULAR PATHOLOGY UNIT
J. Keith Joung, MD, PhD

Associate Chief of Pathology (Research),
The Jim and Ann Orr MGH Research Scholar, and
Director, Molecular Pathology Unit, Massachusetts General Hospital

Phone: 617-726-9462 • http://www.jounglab.org
Selected Publications
“Customizable DNA targeting technologies have important applications
Tsai SQ, Wyvekens N, Khayter C, Foden JA,
Thapar V, Reyon D, Goodwin MJ, Aryee MJ, in biological research and gene therapy…”
Joung JK. Dimeric CRISPR RNA-guided FokI
nucleases for high specific genome editing.
Nat Biotechnol., 2014 Jun;32(6): 569-7.
Sander JD, Joung JK. CRISPR-Cas systems for The Joung laboratory is developing strategies to reprogram the genome and epigenome
editing, regulating and targeting genomes. of living cells to better understand biology and treat disease. We have developed and
Nat Biotechnol. 2014 Apr;32(4):347-55. optimized molecular tools for customized genome editing that enable scientists to alter
Review. the DNA sequence of a living cell—from fruit flies to humans—with great precision. These
Fu Y, Sander JD, Reyon D, Cascio V, Joung JK.
technologies are based on proteins engineered to recognize and cleave specific genomic
Improving CRISPR-Cas nuclease specificity sequences. We also use these targeting methodologies to enable activation, repression,
using truncated guide RNAs. Nat Biotechnol., or alteration of histone modifications of specific genes. These tools have many potential
2014 Mar;32(3):279-84. research uses and may one day lead to more efficient gene therapy capable of correcting
disease-related mutations in human cells.
Maeder ML, Angstman JF, Richardson ME,
Linder SJ, Cascio VM, Tsai SQ, Ho QH,
Sander JD, Reyon D, Bernstein BE, Costello Genome Editing Using Targeted Nucleases
JF, Wilkinson MF, Joung JK. Targeted DNA Genome editing technology was recently named runner-up for “Breakthrough of the
Demethylation and Endogenous Gene Year” for 2012 and 2013 by Science magazine and “Method of the Year” for 2011 by Nature
Activation Using Programmable TALE- Methods. We have previously described two rapid, robust, and publicly available methods
TET1 Fusions. Nat Biotechnol., 2013 Dec; for engineering ZFNs known as OPEN (Oligomerized Pool Engineering; Maeder et al., Mol
31(12):1137-42.
Cell 2008) and CoDA (Context-Dependent Assembly; Sander et al., Nat Methods 2011). In
Fu Y, Foden JA, Khayter C, Maeder ML, addition, we have also developed and optimized methods for engineering TALENs including
Reyon D, Joung JK*, Sander JD*. High- an automated, high-throughput method known as FLASH (Fast Ligation-based Automated
frequency off-target mutagenesis induced by Solid-phase High-throughput) assembly (Reyon et al., Nat Biotechnol. 2012). We have also
CRISPR-Cas nucleases in human cells. Nat recently described reagents that enable the rapid construction of CRISPR RNA-guided
Biotechnol. 2013 Jun 23. *Co-corresponding
authors
nucleases (RGNs) (Hwang et al., Nat Biotechnol. 2013).
Much of our recent work has focused on CRISPR RGNs. We and our collaborators were the
Hwang WY, Fu Y, Reyon D, Maeder ML, Tsai
SQ, Sander JD, Peterson RT, Yeh JR, Joung first to demonstrate that RGNs can function in vivo (Hwang & Fu et al., Nat Biotechnol.
JK. Efficient genome editing in zebrafish 2013) and the first to show that they can induce significant off-target mutations in human
using a CRISPR-Cas system. Nat Biotechnol. cells (Fu et al., Nat Biotechnol. 2013). We have developed two platforms that improve
2013 Mar;31(3):227-9. RGN specificities: one based on the use of truncated guide RNAs (Fu & Sander et al., Nat
Biotechnol. 2014) and the other in which we engineered dimerization-dependent CRISPR
RNA-guided nucleases (Tsai et al., Nat Biotechnol. 2014).
Epigenome Editing Using Targeted Transcription Factors

We have recently demonstrated that the TALE and CRISPR platforms can also be utilized to
create artificial transcription factors that can robustly alter expression of endogenous human
genes (Maeder et al., Nat Methods 2013a; Maeder et al., Nat Methods 2013b). In addition, we
have collaborated with Brad Bernstein’s group to develop fusions of the histone demethylase
LSD1 with TALE domains that can induce targeted histone alterations at endogenous human
enhancers (Mendenhall et al., Nat Biotechnol. 2013). Finally, we have also developed fusions
of engineered TALE domains with the catalytic domain of the TET1 enzyme, enabling the
targeted demethylation of CpGs in human cells (Maeder et al., Nat Biotechnol. 2013).
1| MGH PATHOLOGY
David M. Langenau, PhD

Assistant Professor of Pathology, Harvard Medical School
Associate Director, Molecular Pathology Unit, Massachusetts General Hospital
Member, Harvard Stem Cell Institute

Charlestown MA 02129
Tel: 617-643-6508 • Fax: 617-726-5684
dlangenau@mgh.harvard.edu • http://langenaulab.com
“Identifying molecular pathways that drive progression and relapse in
Tang Q, Abdelfattah NS, Blackburn JS, Moore
JC, Martinez SA, Moore FE, Lobbardi R, pediatric cancer…”
Tenente IM, Ignatius MS, Berman JN, Liwski
RS, Houvras Y, Langenau DM. Optimized
cell transplantation using adult rag2 mutant
zebrafish. Nature Methods. 2014;
The Langenau laboratory research focus is to uncover relapse mechanisms in pediatric cancer.
11(8):821-4.
Utilizing zebrafish models of T-cell acute lymphoblastic leukemia (T-ALL) and embryonal
Blackburn JS, Liu S, Wilder JL, Dobrinski rhabdomysoarcoma (ERMS), we have undertaken chemical and genetic approaches to
KP, Lobbardi R, Moore FE, Martinez SA, identify novel modulators of progression, therapy-resistance, and relapse.
Chen EY, Lee C, Langenau DM. Clonal
evolution enhances leukemia propagating
Uncovering progression-associated driver mutations in T-cell acute lymphoblastic leukemia
cell frequency in T-cell acute lymphoblastic
leukemia through AKT/mTORC1 pathway T-ALL is an aggressive malignancy of thymocytes that affects thousands of children and adults
activation. Cancer Cell. 2014; 25(3):366-78. in the United States each year. Recent advancements in conventional chemotherapies have
improved the five-year survival rate of patients with T-ALL. However, patients with relapse
Chen EY, DeRan M, Ignatius MS, Grandinetti disease are largely unresponsive to additional therapy and have a very poor prognosis.
KB, Clagg R, McCarthy K, Lobbardi RM,
Ultimately, 70% of children and 92% of adults will die of relapse T-ALL, underscoring the
Brockmann J, Keller C, Wu X, Langenau
DM. GSK3 inhibitors induce the canonical clinical imperative for identifying the molecular mechanisms that cause leukemia cells to re-
WNT/b-catenin pathway to suppress emerge at relapse. Utilizing a novel zebrafish model of relapse T-ALL, large-scale trangenesis
growth and self-renewal in embryonal platforms, and unbiased bioinformatic approaches, we have uncovered new oncogenic
rhabdomyosarcoma. PNAS. 2014; drivers associated with aggression, therapy resistance and relapse. A large subset of these
111(14):5349-54. genes exert important roles in regulating human T-ALL. Discovering novel relapse-driving
Chen EY, Dobrinski KP, Brown KH, Clagg oncogenic pathways will likely identify new drug targets for the treatment of T-ALL.
R, Edelman E, Ignatius MS, Brockmann J,
Nielsen GP, Ramaswamy S, Keller C, Lee Visualizing and killing cancer stem cells in embryonal rhabdomyosarcoma
C, Langenau DM. Cross-species Array ERMS is a common soft-tissue sarcoma of childhood and phenotypically recapitulates fetal
Comparative Genomic Hybridization muscle development arrested at early stages of differentiation. Microarray gene expression
Identifies Novel Oncogenic Events
studies and cross-species comparisons of zebrafish, mouse and human ERMS uncovered RAS
in Zebrafish and Human Embryonal
Rhabdomyosarcoma, PLoS Genetics. 2013; as the dominant oncogenic pathway in ERMS. Building on this discovery, our laboratory
9(8):e1003727. has developed a transgenic zebrafish model of kRASG12D-induced ERMS that mimics the
molecular underpinnings of human ERMS. We have used fluorescent transgenic zebrafish
Ignatius MS, Chen E, Elpek NE, Fuller A, to label ERMS cell subpopulations based on myogenic factor expression and identified
Tenente IM, Clagg R, Liu S, Blackburn JS,
functionally distinct classes of tumor cells contained within the ERMS mass. Specifically, the
Linardic CM, Rosenberg A, Nielsen PG,
Mempel TR, Langenau DM. In vivo imaging myf5-GFP+ self-renewing cancer stem cell drives continued tumor growth at relapse and is
of tumor-propagating cells, regional tumor molecularly similar to a non-transformed, activated muscle satellite cell. Our laboratory has
heterogeneity, and dynamic cell movements undertaken chemical genetic approaches to identify drugs that kill relapse-associated, self-
in embryonal rhabdomyosarcoma. Cancer renewing myf5-GFP+ ERMS cells. We are currently assessing a subset of drugs for their ability
Cell. 2012; 21(5):680-93. to regulate growth of human ERMS cells.
Smith AC, Raimondi AR, Salthouse CD,
Ignatius MS, Blackburn JS, Mizgirev IV, Storer
NY, de Jong JL, Chen AT, Zhou Y, Revskoy
S, Zon LI, Langenau DM. High-throughput
cell transplantation establishes that tumor-
initiating cells are abundant in zebrafish
T-cell acute lymphoblastic leukemia. Blood.
2010; 115(16):3296-303.
MGH PATHOLOGY | 2
Martin Aryee, PhD

Assistant Molecular Pathologist, Massachusetts General Hospital

Phone: 617-726-5690
Minfi: a flexible and comprehensive Computational methods for genomics and epigenomics...
Bioconductor package for the analysis of
Infinium DNA methylation microarrays. Aryee
MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta
C, Feinberg AP, Hansen KD, Irizarry RA.
Bioinformatics. 2014;30(10):1363-9.
My research involves computational methods that enable us to elucidate the genetic and
Aryee MJ, Liu W, Engelmann JC, Nuhn P, epigenetic basis of cancer and other diseases from large genomic datasets.
Gurel M, Haffner MC, Esopi D, Irizarry RA,
Getzenberg RH, Nelson WG, Luo J, Xu J, Tumor Heterogeneity: We develop statistical methods to improve our understanding of
Isaacs WB, Bova GS, Yegnasubramanian tumor cell-to-cell variability and its relationship to cancer progression. Much of this work
S. DNA methylation alterations exhibit
relates to the computational and statistical challenges posed by single-cell transcriptome and
intraindividual stability and interindividual
heterogeneity in prostate cancer metastases. epigenome data.
Sci Transl Med. 2013;5(169):169ra10. Different tumors, even of the same type, can harbor extremely heterogeneous genetic and
Liu Y*, Aryee MJ*, Padyukov L, Fallin epigenetic alterations. To investigate the role of epigenetic stochasticity in cancer, we recently
MD, Hesselberg E, Runarsson A, Reinius applied a statistical model to study patterns of inter- and intra-individual tumor heterogeneity
L, Acevedo N, Taub M, Ronninger M, during metastasis. We established that metastatic prostate cancer patients develop distinctly
Shchetynsky K, Scheynius A, Kere J, unique DNA methylation signatures that are subsequently maintained across metastatic
Alfredsson L, Klareskog L, Ekström TJ, dissemination. The stability of these individualized DNA methylation profiles has implications
Feinberg AP. Epigenome-wide association
for the promise of epigenetic alterations as diagnostic and therapeutic targets in cancer.
data implicate DNA methylation as an
intermediary of genetic risk in rheumatoid
arthritis. Nat Biotechnol. 2013;31(2):142-7. Epigenome Mapping: Unlike genome sequencing which has well established experimental
and analytical protocols, epigenome mapping strategies are still in their infancy and, like
Aryee MJ, Wu Z, Ladd-Acosta C, Herb B, other high-throughput techniques, are plagued by technical artifacts. A central theme of
Feinberg AP, Yegnasubramanian S, Irizarry
our research involves the development of methods for extracting signal from noisy high-
RA. Accurate genome-scale percentage DNA
methylation estimates from microarray data. throughput genomic assays. The goal of such preprocessing methods is to transform raw data
Biostatistics. 2011;12(2):197-210. from high-throughput assays into reliable measures of the underlying biological process.
Until recently, studies of DNA methylation in cancer had focused almost exclusively on CpG
Wu Z, Aryee MJ. Subset quantile dense regions in gene promoters. We helped develop the statistical tools used to analyze the
normalization using negative control
first genome-scale DNA methylation assays designed without bias towards CpG islands. These
features. J Comput Biol.
2010;17(10):1385-95. tools enabled the discovery that the majority of both tissue-specific and cancer-associated
variation occurs in regions outside of CpG islands. We showed that there is a strong overlap
between genomic regions involved in normal tissue differentiation, reprogramming during
induced pluripotency, and cancer.
Epigenomic Studies of Complex Disease: Despite the discovery of numerous disease-associated

genetic variants, the majority of phenotypic variance remains unexplained for most diseases,
suggesting that non-genetic factors play a significant role. Part of the explanation will lie in
a better understanding of epigenetic mechanisms. These mechanisms are influenced by both
genetic and environmental effects and, as downstream effectors of these factors, may be more
directly related to phenotype. However, the broad extent of epigenetic dysregulation in cancer
and many other diseases complicates the search for the small subset of alterations with a causal
role in pathogenesis. We are developing computational methods to integrate genome-wide
genetic and epigenetic data with the goal of identifying the subset of functionally important
epigenetic alterations.
3| MGH PATHOLOGY
Atul K. Bhan, MBBS, MD

Professor of Pathology, Harvard Medical School
Pathologist, Massachusetts General Hospital

55 Fruit Street
Warren Building, Room 501
Boston, MA 02114
Phone: 617-726-2588 • Fax: 617-726-2365
Email: abhan@partners.org
Lassen KG, Kuballa P, Conway KL, et al. “Researching mucosal immunology and inflammatory bowel disease...”
Atg16L1 T300A variant decreases selective
autophagy resulting in altered cytokine
signaling and decreased antibacterial
defense. Proc Natl Acad Sci U S A
2014;111:7741-6.
In the two major forms of IBD, Crohn’s disease and ulcerative colitis the underlying etiological
Shouval DS, Biswas A, Goettel JA, et al. factors and the pathogenesis remain poorly defined. It is generally believed that exaggerated
Interleukin-10 receptor signaling in innate immune responses to luminal normal enteric flora are involved in the initiation and
immune cells regulates mucosal immune perpetuation of the disease process.
tolerance and anti-inflammatory macrophage
function. Immunity 2014;40:706-19.
The availability of a wide variety of experimental models of intestinal inflammation has
Kaliannan K, Hamarneh SR, Economopoulos helped provide important clues about the pathogenesis of IBD. The commonly used models
KP, et al. Intestinal alkaline phosphatase include chemically induced mucosal injury and colitis induced by the transfer of selected
prevents metabolic syndrome in mice. Proc populations of T cells into immunodeficient mice. The spontaneous development of colitis
Natl Acad Sci U S A. 2013;110:7003-8. in genetically engineered animal models have provided excellent experimental models to
Chang SY, Song JH, Guleng B, et al. study the pathogenesis of IBD. One important lesson learned from IBD models is that many
Circulatory antigen processing by mucosal different immunologic and mucosal defects can lead to similar pathologic findings.
dendritic cells controls CD8+ T cell. Immunity
2013;38:153-165. For the last several years, our laboratory has focused on defining the pathogenesis of chronic
Yilmaz OH, Katajisto P, Lamming DW, et al. intestinal inflammation using TCR alpha KO mice as a model of human IBD. TCR alpha KO
mTORC1 in the Paneth cell niche couples mice develop spontaneously chronic colitis with many features of ulcerative colitis. We have
intestinal stem-cell function to calorie intake. identified a regulatory B cell subset, which appears under chronic intestinal inflammatory
Nature 2012;486:490-5. conditions and suppresses the progression of intestinal inflammation by secreting IL-10. TCR
alpha KO mice deficient in both IL-4 and B cells, but not in IL-4 alone, develop granulomatous
Sugimoto K, Ogawa A, Shimomura Y, et al.
Inducible IL-12-producing B cells regulate colitis with features of Crohn’s disease. This suggests that differences in the two major forms
Th2-mediated intestinal inflammation. of IBD may reflect different immunological responses to similar initiating events.
Gastroenterology 2007;133:124-36.
The laboratory is closely associated with the Center for the Study of Inflammatory Bowel
Mizoguchi A, Ogawa A, Takedatsu H, et
Disease at MGH and collaborates with the other members of the Center; Dr. Bhan is an
al. Dependence of intestinal granuloma
formation on unique myeloid DC-like cells. Associate Director of the Center. In collaboration with Dr. Terhorst and Dr. Xavier we have
J Clin Invest 2007;117:605-615. studied the role of Th-1 and Th-17 pathways, innate immune system and autophagy in the
development of intestinal inflammation. Collaborative studies with Dr. Scott Snapper’s
laboratory have shown that interleukin10 receptor signaling in innate immune cells regulates
mucosal immune tolerance and anti-inflammatory macrophage function. The studies with
Dr. Richard Hodin’s laboratory indicate that administration of intestinal alkaline phosphatase
may have a beneficial effect in intestinal inflammatory conditions and metabolic syndromes.
Dr. Bhan’s consultant role in the newly established Harvard Institute of Translational
Immunology-Helmsley Pilot Program in Crohn’s Disease has led to his collaboration with
Dr. Vijay Yajnik at MGH and Dr. Matthew Myerson at DFCI to identify microorganisms in
Crohn’s disease lesions.
MGH PATHOLOGY | 4
A. John Iafrate, MD, PhD

Associate Pathologist, Massachusetts General Hospital
Associate Chief of Pathology, Center for Integrated Diagnostics

55 Fruit Street
Boston, MA 02114
Phone: 617-726-0166 • Fax: 617-726-5079 • Email: aiafrate@partners.org
Zheng Z, Liebers M, Zhelyazkova B, Cao Y, “Identifying large-scale copy number variants in the human genome...”
Panditi D, Chen J, Robinson HE, Chmielecki
J, Pao W, Engelman JA, Iafrate AJ, Le LP.
Anchored multiplex PCR for targeted next-
generation sequencing. Nat Medicine,
in press.
Our lab has focused efforts on translating highly complex molecular analyses of tumor
Snuderl M, Fazlollahi L, Le LP, Nitta M, genetics using novel technologies into clinical use. We have previously developed the
Zhelyazkova BH, Davidson CJ, Akhavanfard SNaPshot genotyping assay, which has enabled Mass General to make personalized cancer
S, Cahill DP, Aldape KD, Betensky RA, Louis medicine a priority. We have a strong interest in the clinical implementation of genetic
DN, Iafrate AJ: Mosaic amplification of screening technologies that can help direct targeted therapies, focusing on lung, pancreatic
multiple receptor tyrosine kinase genes in
and brain tumors. Our recent contributions in the treatment of a subset of lung tumors with
glioblastoma. Cancer Cell 20:810-7, 2011.
rearrangements of the ALK tyrosine kinase and with rearrangements of the ROS1 tyrosine
Bergethon K, Shaw AT, Ignatius Ou SH, kinase with a small molecule kinase inhibitor underscore the promise of personalized cancer
Katayama R, Lovly CM, McDonald NT, care. Our long term goal is to develop high-throughput genetic screening approaches for all
Massion PP, Siwak-Tapp C, Gonzalez A, cancer patients. To address this need, we have developed a novel next generation sequencing
Fang R, Mark EJ, Batten JM, Chen H, Wilner
technique termed “anchored multiplex PCR (AMP)”, that is especially powerful at detection
KD, Kwak EL, Clark JW, Carbone DP, Ji H,
Engelman JA, Mino-Kenudson M, Pao W, gene fusion events from clinical specimens. We have shown that AMP is a sensitive as FISH
Iafrate AJ: ROS1 Rearrangements Define a in diagnosing ALK, ROS1 and RET fusions in lung cancer, and does not require knowing both
Unique Molecular Class of Lung Cancers. fusion partners. In addition, AMP can be used for genomic DNA target enrichment, and is
J Clin Oncol 30(8):863-70, 2012. scalable and cost effective.
Kwak EL, Bang Y, Camidge DR, ShawAT,
Solomon B, Maki RG, Ou SI, Dezube BJ, We have also continued prior studies of tumor heterogeneity, by studying gene amplification
Jänne PA, Costa DB, Varella-Garcia M, Kim of receptor tyrosine kinases in glioblastoma. This work has revealed a new subclass of brain
W, Lynch TJ, Fidias P, Stubbs H, Engelman tumors with mosaic gene amplification of up to 3 kinases in distinct but intermingled cell
JA, Sequist LV, Tan W, Gandhi L, Mino- populations within the same tumor. We are exploring the therapeutic implications of such
Kenudson M, Wei GC, Shreeve SM, Ratain driver gene heterogeneity in model systems of glioblastoma using patient derived cell lines
MJ, Settleman J, Christensen JG, Haber DA,
and xenografts.
Wilner K, Salgia R, Shapiro GI, Clark JW,
Iafrate AJ. Response of non-small cell lung
cancers with Anaplastic Lymphoma Kinase Our laboratory has also focused on human germline genetics, namely on copy number
(ALK) gene rearrangements to a targeted variation (CNVs). These polymorphisms involve copy number gains or losses of large genomic
ALK inhibitor. N Engl J Med 363(18):1693- regions (kilobases up to several megabases), and were identified using high-resolution
703, 2010. genomic microarrays to compare the genomes of phenotypically normal individuals. Our
Dias-Santagata D, Akhavanfard S, David continuing work is focused on the detailed structural analysis of CNVs using high resolution
SS, Vernovsky K, Kuhlmann G, Boisvert SL, fluorescence microscopy imaging techniques, quantitative PCR and BAC sequencing. We have
Stubbs H, McDermott U, Settleman J, Kwak developed novel FISH probes based on deletion CNVs that can be used to determine genetic
EL, Clark JW, Isakoff SJ, Sequist LV, Engelman identity in situ. These probes are being applied to chimerism analysis in transplantation and
JA, Lynch TJ, Haber DA, Louis DN, Ellisen will aid in the study of engraftment, rejection, and graft versus host disease. Importantly,
LW, Borger DR, Iafrate AJ. Rapid targeted
these probes are located on autosomes, so for the first time chimerism analysis can be
mutational analysis of human tumours: a
clinical platform to guide personalized cancer performed in same sex transplants.
medicine. EMBO Mol Med. 2(5):146-58,
2010.
Iafrate AJ, Feuk L., Rivera MN, Listewnik

ML, Donahoe PK, Qi Y, Scherer SW, Lee C.
Detection of large-scale variation in the
human genome. Nat. Genet. 36(9):949-51,
2004.
5| MGH PATHOLOGY
David N. Louis, MD
Benjamin Castleman Professor of Pathology, Harvard Medical School
Pathologist-in-Chief, Massachusetts General Hospital
Pathology Service
55 Fruit Street (WRN-2)
Boston, MA 02114
“Elucidating the molecular basis of glioma formation may impact both
Louis DN. Perry A, Burger P, et al.
International Society of Neuropathology- diagnostic and therapeutic aspects of clinical neuro-oncology…”
Haarlem consensus guidelines for nervous
system tumor classification and grading.
Brain Pathol (in press).
Suvà ML, Rheinbay E, Gillespie SM, Patel We have demonstrated alterations characteristic of specific glioma subtypes and grades.
AP, Riggi N. Wakimoto H, Rabkin SD, We originally demonstrated that molecular genetic analysis could be used to define
Martuza RL, Chi AS, Rivera MN, Wortman clinicopathologically relevant subsets of glioblastomas. We have also shown that molecular
I, Shalek A, Rozenblatt-Rosen O, Regev genetic alterations are powerful predictors of therapeutic response and survival in patients
A, Louis DN, Bernstein BE. Reconstructing with anaplastic oligodendrogliomas and in other oligodendroglial tumors. These findings
and reprogramming the tumor-propagating
have already led to incorporation of molecular diagnostic testing around the world for
potential of glioblastoma stem-like cells.
Cell (in press). these parameters. Dr. Louis has been working to incorporate molecular testing into the next
updates of the World Health Organization Classification of Central Nervous System Tumors.
Chi AS, Batchelor TT, Yang D, Dias-Santagata The lab has also demonstrated that glioblastomas treated with the alkylating agent
D, Borger D, Ellisen L, Iafrate AJ, Louis DN. temozolomide (which is now the standard of care for such cases) frequently inactivate
BRAF V600E mutation identifies a subset
mismatch repair genes, leading to more rapid growth during therapy and to therapeutic
of low-grade diffusely infiltrating gliomas in
adults. J Clin Oncol 31: e233-e236, 2013. resistance, and has worked collaboratively on epigenetic and single-cell studies of high-grade
gliomas.
Camelo-Piragua S, Jansen M, Ganguly A, Kim
JCM, Cosper AK, Dias-Santagata D, Nutt CL, The laboratory has also been involved in molecular genetic studies of other forms of human
Iafrate AJ, Louis DN. A sensitive and specific
diagnostic panel to distinguish diffuse
brain tumors, such as meningiomas.
astrocytoma from astrocytosis: chromosome
7 gain with mutant IDH1 and p53.
J Neuropathol Exp Neurol 70:110-115, 2011.
Yip S, Miao J, Cahill DP, Iafrate AJ, Aldape K,

Nutt CL, Louis DN. MSH6 mutations arise in
glioblastomas during temozolomide therapy
and mediate temozolomide resistance.
Clin Cancer Res 15:4622-9, 2009.
Cahill DP, Levine KK, Betensky RA, Codd PJ,

Romany CA, Reavie LB, Batchelor TT, Futreal
PA, Stratton MR, Curry WT, Iafrate JA, Louis
DN. Loss of the mismatch repair protein
MSH6 in human glioblastomas is associated
with tumor progression during temozolomide
treatment. Clin Cancer Res 13:2038-2045,
2007.
MGH PATHOLOGY | 6
Miguel Rivera, MD
Assistant in Pathology, Massachusetts General Hospital
Associate Member, Broad Institute

Phone: 617-726-6257 • Email: mnrivera@partners.org
Akhavanfard S, Vargas SO, Han MJ, Nitta
“Using genomics to identify critical pathways in pediatric tumors
M, Chang CB, Le LP, Fazlollahi L, Nguyen and sarcomas…”
Q, Ma Y, Cosper A, Dias-Santagata D, Han
JY, Bergethon K, Borger DR, Ellisen LW,
Pomeroy SL, Haber DA, Iafrate AJ, Rivera
MN. Inactivation of the tumor suppressor
Our research focuses on the identification and characterization of critical pathways in
WTX in a subset of pediatric tumors.
Genes Chromosomes and Cancer, 2014 pediatric tumors and sarcomas. An important feature shared by these tumors is their
Jan;53(1):67-77. doi: 10.1002/gcc.22118. strong association with developmental processes and, in particular, with the mechanisms
Epub 2013 Nov 5. PMID: 24249259. that regulate stem cell populations during organ formation. Our work combines the use
of genomic technologies for direct analysis of tumors with functional analysis of pathways
Kim WJ, Rivera MN, Coffman EJ, Haber
that are common to embryonic development and cancer. Given that these developmental
DA. The WTX tumor suppressor enhances
p53 acetylation by CBP/p300. Mol Cell. processes are poorly understood at present, we anticipate that our work will point to new
45(5):587-97, 2012 Mar 9. approaches for therapeutic intervention.
Moisan A*, Rivera MN*, Lotinun S, Role of the WTX gene family in cancer and development
Akhavanfard S, Coffman EJ, Cook EB,
Wilms tumor, the most common pediatric kidney cancer, arises from kidney-specific stem
Stoykova S, Mukherjee S, Schoonmaker JA,
Burger A, Kim WJ, Kronenberg HM, Baron cells and is a prime example of the connection between cancer and development. Through
R, Haber DA, Bardeesy N. The WTX tumor mapping genomic deletions in Wilms tumor we identified WTX, an X-linked tumor suppressor
suppressor regulates mesenchymal progenitor gene commonly inactivated in this disease and recently implicated in other tumor types. WTX
cell fate specification. Dev Cell. 20(5):583-96, is the founding member of a new protein family (FAM123) and our work using a conditional
2011 May 17. *co-authors knockout mouse model has shown that it regulates mesenchymal stem cells in several organs,
Aiden AP*, Rivera MN*, Rheinbay E, Ku including kidneys, bones and fat. We are now studying the function of WTX and related
M, Coffman EJ, Truong TT, Vargas SO, proteins using several in vitro and in vivo model systems.
Lander ES, Haber DA, Bernstein BE. Wilms
tumor chromatin profiles highlight stem Epigenomic approaches to the identification of novel pathways in cancer
cell properties and a renal developmental Genome-wide chromatin profiling, which combines chromatin immunoprecipitation and
network. Cell Stem Cell. 6(6):591-602,
high-throughput sequencing, is a new technology that has been used to study epigenetic
2010 Jun 4. *co-authors
states in embryonic stem cells. As opposed to expression arrays, chromatin profiling provides
Rivera MN*, Kim WJ*, Wells J, Stone A, Burger a unique view of cellular differentiation programs by allowing the identification of both
A, Coffman EJ, Zhang J, Haber DA. The tumor active and repressed domains based on patterns of histone modification. We first applied this
suppressor WTX shuttles to the nucleus and technology to Wilms tumor and identified a stem cell-like pattern of gene regulation that
modulates WT1 activity. Proc Natl Acad Sci U
points to key pathways in this disease. We have now extended our epigenomic analysis to
S A. 106(20):8338-43, 2009 May 19.
*co-authors other tumor types where developmental pathways play a key role.
Rivera MN, Kim WJ, Wells J, Driscoll DR,

Brannigan BW, Han M, Kim JC, Feinberg
AP, Gerald WL, Vargas SO, Chin L, Iafrate
AJ, Bell DW, Haber DA. An X chromosome
gene, WTX, is commonly inactivated in Wilms
tumor. Science. 315(5812):642-5, 2007 Feb 2.
7| MGH PATHOLOGY
Dennis C. Sgroi, MD
Director of Breast Pathology and

Phone: 617-726-5697 • Fax: 617-726-5684 • Email: dsgroi@partners.org
McMullin RP, Wittner BS, Yang C, Denton-
“Understanding the molecular genetic events associated with the
Schneider BR, Hicks D, Singavarapu R, Moulis pathogenesis of human breast cancer...”
S, Lee J, Akbari MR, Narod SA, Aldape
KD, Steeg PS, Ramaswamy S, and Sgroi
DC. A BRCA1 Deficient-Like Signature is
Enriched In Breast Cancer Brain Metastases
The overarching goals of research in the Sgroi laboratory are to develop better ways to
and Predicts DNA Damage-Induced PARP
Inhibitor Sensitivity. Breast Cancer Res. identify patients who are at risk for the development of breast cancer and to identify those
2014; 16(2):R25. breast cancer patients who are likely to benefit from targeted drug therapies. We are taking
several different approaches to achieving these goals. First, we are deciphering specific
Sgroi, DC, Sestak I, Cuzick J, Zhang Y, molecular events that occur during the earliest stages of tumor development and using this
Schnabel CA, Schroeder B, Erlander MG,
knowledge to develop biomarkers that will predict for increased risk of progression to cancer.
Dunbier A, Sidhu K, Lopez-Knowles E, Goss
PE, and Dowsett M. Prediction of late distant Second, using advance molecular technologies, we are searching for novel breast cancer
recurrence in patients with oestrogen- biomarkers to identify patients with hormone-receptor-positive breast cancer who are most
receptor-positive breast cancer: a prospective likely to benefit from extended hormonal therapy and from novel targeted therapeutics.
comparison of the Breast Cancer Index (BCI)
assay, 21-gene recurrence score, and IHC4 in My research focuses on understanding the molecular genetic events associated with
TransATAC study population. Lancet Oncol. the pathogenesis of human breast cancer. My laboratory has developed technological
2013;14(11):1067-76.
approaches to study gene expression in the earliest microscopic precursor lesions as well
Sgroi DC, Carney E, Zarrella E, Steffel L, as in the latest stages of human breast cancer. Specifically, we have been successful in
Binns SN, Finkelstein DM, Szymonifka J, combining laser capture microdissection, high-density cDNA arrays and real-time quantitative
Bhan AK, Shepherd LE, Zhang Y, Schnabel PCR and advanced tandem mass spectrometry technologies to identify novel gene and
CA, Erlander MG, Ingle JN, Porter P, Muss
protein expression patterns in human breast cancer. We have shown that the various
HB, Pritchard KI, Tu D, Rimm DL, Goss PE.
Prediction of Late Disease Recurrence and pathological stages of breast cancer progression are highly similar at the transcriptional
Extended Adjuvant Letrozole Benefit by the level, and that atypical intraductal hyperplasia—the earliest identifiable stage of breast
HOXB13/IL17BR Biomarker. J Natl Cancer cancer—is a genetically advanced lesion with an expression profile that resembles that of
Inst. 2013; 105:1036-1042. invasive breast cancer. More recently, we have studied the gene expression changes of the
stromal microenvironment during breast cancer progression, and we demonstrated that the
Zhang Y, Schnabel CA, Schroeder BE,
Jerevall PL, Jankowitz RC, Fornander T, Stal transition from preinvasive to invasive breast cancer is associated with distinct stromal gene
O, Brufsky AM, Sgroi D, Erlander M. Breast expression changes.
Cancer Index Identifies Early Stage ER+
Breast Cancer Patients at Risk for Early and Presently, my laboratory is focused on applying high-throughput DNA microarray and
Late Distant Recurrence. Clin Cancer Res. proteomic technologies as a means to predict the clinical behavior of human breast cancer in
2013;19(15):4196-205. the setting of hormonal and chemotherapeutic regimens. We have independently developed
Imielinski M, Cha S, Rejtar T, Richardson two complementary biomarkers—the Molecular Grade Index (MGI) and the HOXB13/IL17BR
EA, Karger BL, Sgroi DC. Integrated (H/I). MGI is a molecular surrogate for histological grade and a highly precise biomarker
proteomic, transcriptomic, and biological for risk of breast cancer recurrence. The HOXB13:IL17BR index is a biomarker of endocrine
network analysis of breast carcinoma reveals responsiveness in ER+ breast cancer, as it has been shown to predict for benefit from
molecular features of tumorigenesis and
adjuvant and extended anti-hormonal therapy. Most recently, we demonstrated that the
clinical relapse. Mol Cell Proteomics.
2012; 11(6):M111.014910. combination MGI and H/I, called the Breast Cancer Index (BCI), outperforms the Oncotype
Dx Recurrence Score for predicting risk of recurrence. As a result of our collective data, we
anticipate assessing BCI in clinical trials of extended adjuvant hormonal therapy. Lastly, we
are currently investigating the functional activity of HOXB13 and assessing its possible role as
a surrogate marker for a nonclassical estrogen receptor signaling pathway.
MGH PATHOLOGY | 8
Anat Stemmer-Rachamimov, MD
Associate Neuropathologist, Massachusetts General Hospital

Phone: 617-726-5510 • Fax: 617-726-5079
Email: astemmerrachamimov@partners.org
Mayes DA, Rizvi TA, Titus-Mitchell H, Oberst “Investigating hereditary brain tumor syndromes...”
R, Ciraolo GM, Vorhees CV, Robinson
AP, Miller SD, Cancelas JA, Stemmer-
Rachamimov AO, Ratner N. Nf1 loss and
Ras hyperactivation in oligodendrocytes
induce NOS-driven defects in myelin and
Our lab’s research focuses on identifying the underlying molecular changes in lesions and
vasculature. Cell Rep. 4(6):1197-212 (2013).
malformations associated with hereditary brain tumor syndromes (neurofibromatosis 1,
Brastianos PK, Horowitz PM, Santagata S, neurofibromatosis 2, schwannomatosis and tuberous sclerosis), and the identification of
Jones RT, McKenna A, Getz G, Ligon KL, activated pathways or events that lead to tumor progression. Although hereditary brain
Palescandolo E, Van Hummelen P, Ducar tumor syndromes are relatively uncommon, the same molecular events and pathways are
MD, Raza A, Sunkavalli A, Macconaill
often involved in tumorigenesis and progression of similar sporadic tumors that are much
LE, Stemmer-Rachamimov AO, Louis DN,
Hahn WC, Dunn IF, Beroukhim R. Genomic more frequent in the general population.
sequencing of meningiomas identifies
oncogenic SMO and AKT1 mutations. For example, Schwannomas are benign nerve sheath tumors that may arise in people with
Nat Genet. 45(3):285-9, (2013). no underlying genetic syndrome (solitary, sporadic schwannomas) or in the context of two
hereditary tumor syndromes; neurofibromatosis 2 and schwannomatosis. Although all
Kalamarides M, Stemmer-Rachamimov AO,
Niwa-Kawakita M, Chareyre F, Taranchon E, schwannomas share the loss of function of the NF2 gene, our hypothesis is that additional,
Han ZY, Martinelli C, Lusis EA, Hegedus B, epigenetic events occur in Schwannomas and are responsible for the clinical manifestations
Gutmann DH, Giovannini M. Identification associated with these tumors such as pain, hearing loss or rapid tumor growth. The
of a progenitor cell of origin capable of identification of these events and of the pathways involved (by microarray expression
generating diverse meningioma histological analyses) may aid in the diagnosis of the different subclinical types of schwannomas as well as
subtypes. Oncogene 30(20):2333-44,
in the development of targeted therapies. Our recent work in collaboration with researchers
(2011).
and clinicians in MGH has unraveled molecular pathways of angiogenesis in schwannomas,
Plotkin SR, Stemmer-Rachamimov AO, Barker leading to targeted antiangiogenesis therapy with clinical improvement in a small series of
FG 2nd, Halpin C, Padera TP, Tyrrell A, patients with NF2-associated schwannomas.
Sorensen AG, Jain RK, di Tomaso E. Hearing
improvement after bevacizumab in patients
Finally, in collaboration with multiple groups, we perform extensive pathological analyses
with neurofibromatosis type 2. N Engl J Med
23;361(4):358-67 (2009). of new mouse models of neurofibromatoses. These models continue to shed light on the
biology and pathogenesis of neurofibromatoses as well as provide a useful platform for novel
Stankovic KM, Mrugala MM, Martuza RL, drug trials.
Silver M, Betensky RA, Nadol JB Jr, Stemmer-
Rachamimov AO. Genetic determinants
of hearing loss associated with vestibular
schwannomas. Otol Neurotol. 30(5):661-7
(2009).
9| MGH PATHOLOGY
Mario L. Suvà, MD, PhD


suva.mario@mgh.harvard.edu
“Stem cell programs, epigenetic dependencies and cellular heterogeneity
Patel AP, Tirosh I, Trombetta JJ, Shalek
AK, Gillespie SM, Wakimoto H, Cahill DP, in gliomas...”
Nahed BV, Curry WT, Martuza RL, Louis
DN, Rozenblatt-Rosen O, Suvà ML*, Regev
A*, Bernstein BE*. Single-cell RNA-seq
highlights intra-tumoral heterogeneity
Our laboratory studies the biology of brain tumors, in particular glioblastoma and
in primary glioblastoma. Science. 2014;
344(6190):1396-401. (*equal contribution) oligodendroglioma. Our research focus is to uncover how cellular heterogeneity and
plasticity contribute to tumorigenesis and progression. We study primary human samples
Suvà ML*, Rheinbay E*, Gillespie SM, at single-cell resolution and establish genetically and epigenetically relevant cellular models
Patel AP, Wakimoto H, Rabkin SD, Chi AS, from patient tumors. We model how brain cancer cells exploit their plasticity to establish
Cahill DP, Nahed BV, Curry WT, Martuza
distinct epigenetic programs. Additionally, the laboratory investigates how genetic events
RL, Rivera MN, Riggi N, Rossetti N, Kasif
S, Beik S, Kadri S, Tirosh I, Wortman I, affect genes involved in chromatin regulation to rewire cancer cells and contribute to cellular
Shalek A, Rozenblatt-Rosen O, Regev A, transformation. We seek to identify common programs that would offer novel therapeutic
Louis DN, Bernstein BE. Reconstructing options for patients with glioma.
and reprogramming the tumor propagating
potential of glioblastoma stem-like cells. Cell. Annotation of functional genomic elements in secondary glioblastoma,
2014; 157(3):525-7. (*equal contribution) pediatric glioblastoma and oligodendroglioma
Rheinbay E*, Suvà ML*, Gillespie SM, We have performed chromatin landscape profiling of primary glioblastoma and
Wakimoto H, Patel AP, Shahid M, Oksuz O, reconstructed functionally validated networks that drive continued tumor growth. We are
Rabkin SD, Martuza RL, Rivera MN, Louis applying these novel technologies to genetically defined primary cultures of IDH1 mutant
DN, Kasif S, Chi AS, Bernstein BE. Chromatin glioblastoma, H3F3A mutant pediatric glioblastoma and IDH1 mutant oligodendroglioma
profiles reveal an aberrant transcription
obtained through our collaborations with the MGH Brain Tumor Center.
factor network connected to Wnt signaling
and essential for glioblastoma stem cell
maintenance. Cell Reports. 2013; 3(5):1567- Targeting neurodevelopmental programs in primary human glioblastoma stem cells
79. (*equal contribution) Our work has identified neurodevelopmental transcription factors as master regulators of a
stem-like state in glioblastoma and reconstructed a transcriptional network model. Our lab is
Suvà ML, Riggi N and Bernstein BE.
utilizing genome-editing technologies to generate functional knock-out of critical nodes in
Epigenetic reprogramming in cancer. Science.
2013; 339(6127):1567-70. the network to identify novel dependencies in glioblastoma and to assess novel therapeutic
options.
Janiszewska M*, Suvà ML*, Riggi N,
Houtkooper RH, Auwerx J, Clément-Schatlo Glioma heterogeneity assessed at the single cell level
V, Radovanovic I, Rheinbay E, Provero P,
We are currently transcriptionally profiling single cells from many types of gliomas to assess
Stamenkovic I. Imp2 controls oxidative
phosphorylation and is crucial for preserving tumor heterogeneity at an unprecedented depth.
glioblastoma cancer stem cells. Genes
& Development. 2012; 26(17):1926-44.
(*equal contribution)
MGH PATHOLOGY | 10
HOWARD HUGHES MEDICAL INSTITUTE
Bradley Bernstein, MD, PhD

Associate Member, Broad Institute

185 Cambridge Street
Simches Research Building CPZN 8234
Boston, MA 02114
Phone: 617-726-6906 • Fax: 617-643-3566 • Email: Bernstein.Bradley@mgh.harvard.edu
“Chromatin deregulation can result in inappropriate gene expression
Suva ML, Rheinbay E, Gillespie SM,
Wakimoto H, Cahill DP, Nashed BV, Curry and contribute to the pathogenesis of cancer and other diseases...”
WT, Martuza RL, Louis DN, Rozenblatt-
Rosen O, Suva ML, Regev A Bernstein BE.
Reconstructing and programming the tumor
propagating potential of glioblastoma
The Bernstein laboratory studies how the DNA in the human genome is packaged by a structure
stem-like cells. Cell 157: 580-594 (2014).
called chromatin. A central question in human biology is how a single genome sequence
Patel AP, Tirosh I, Trombetta JJ, Shalek can give rise to the hundreds of different cell types in the body. Scientists understand that
AK, Gillespie SM, Wakimoto H, Cahill DP, differential patterns of gene expression underlie the many different cellular phenotypes seen
Nahed BV, Curry WT, Martuza RL, Louis DN, in multicellular organisms. These different expression patterns and phenotypes are intimately
Rozenblatt-Rosen O, Suva ML, Regev A,
related to the way in which genomic DNA is organized into chromatin in the cell. This
Bernstein BE. Single Cell RNA-seq highlights
intratumoral heterogeneity in primary organizational structure of proteins and DNA, sometimes referred to as the epigenome, helps
glioblastoma. Science 344:1396-1401 control which genes are expressed in a given cell type and is critical to the function of normal
(2014). cells. Notably, the epigenome is inappropriately altered in most—if not all—human cancers.
Suva ML, Riggi N, Bernstein BE. Epigenetic Our long-term goal is to achieve a comprehensive understanding of how chromatin structure,
reprogramming in cancer. Science. transcriptional programs and functional phenotypes inter-relate in developing stem cells and
339:1567-70, (2013). in cancers, such as brain tumors and leukemias.
Zhu J, Adli M, Zou JY, Verstappen G,
Coyne Michael, Zhang X, Durham T, Miri Technologies for mapping histone modifications and chromatin proteins
M, Deshpande V, De Jager PL, Bennett We are combining tools in stem cell biology, biochemistry and genome engineering with
DA, Houmard JA, Muoio DM, Onder TT, next-generation sequencing to achieve increasingly precise, genome-wide views of chromatin
Camahort R, Cowan CA, Meissner A, Epstein structure, chromatin regulator binding and genome organization. Genetic and chemical
CB, Shoresh N, Bernstein BE. Genome-wide perturbations then allow us to test predicted regulatory interactions and functions. Ongoing
chromatin state transitions associated with
projects are applying these approaches to characterize noncoding regulatory elements in the
developmental and environmental cues.
Cell. 152:642–654 (2013). human genome and to understand how the resulting cell circuits control gene expression
programs during development and in cancer. We also leverage emerging single-cell and single-
Ram O, Goren A, Amit I, Shoresh N, Yosef N, molecule techniques to deconvolve heterogeneous cell populations and dynamic processes.
Ernst J, Kellis M, Gymrek M, Issner R, Coyne
M, Durham M, Zhang X, Donaghey J, Epstein
Epigenetic regulation of stem cell differentiation
CB, Regev A, Bernstein BE. Combinatorial
patterning of chromatin regulators uncovered Chromatin regulators play critical roles in controlling the expression and potential of genes
by genome-wide location analysis in human during development. We identified a novel chromatin structure, termed bivalent domains, that
cells. Cell. 147:1628-39 (2011). is subject to simultaneous regulation by Polycomb repressors and trithorax activators. In ES
cells, bivalent domains appear to keep developmental genes poised for alternate fates. We are
Ernst J, Kheradpour P, Mikkelsen TS, Shoresh
now applying emerging chromatin and genome engineering approaches to study how bivalent
N, Ward LD, Epstein CB, Zhang X, Wang L,
Issner R, Coyne M, Ku M, Durham T, Kellis domains and interacting regulatory elements program gene expression in development.
M, Bernstein BE. Mapping and analysis of
chromatin state dynamics in nine human Chromatin regulation in cancer cells
cell types. Nature. 473:43-9 (2011). Genes encoding chromatin regulators are frequently mutated in human cancer. Moreover, cells
in an individual tumor can vary markedly in their epigenetic states, transcriptional outputs,
and functional phenotypes. We seek to understand how epigenetic lesions and epigenetic
heterogeneity contribute to key cancer cell properties, such as tumor propagation, stemness,
and drug resistance. We characterize the transcriptional and epigenetic landscapes of primary
tumors and, in parallel, investigate representative tumor models in the laboratory. These
synergistic approaches can inform therapeutic strategies for targeting epigenetic lesions or
overcoming resistance mechanisms.
11 | MGH PATHOLOGY
HOWARD HUGHES MEDICAL INSTITUTE
Jeannie T. Lee, MD, PhD

Professor of Genetics (Pathology), Harvard Medical School
Molecular Biologist, Massachusetts General Hospital

Simches Research Building
Boston, MA 02114
Phone: 617-726-5943 • Fax: 617-726-6893 • Email: lee@molbio.mgh.harvard.edu
Payer B, Rosenberg M, Yamaji M, Yabuta Y, “The role of long noncoding RNA in epigenomic regulation…”
Koyanagi-Aoi M, Hayashi K, Yamanaka S,
Saitou M, Lee JT. Tsix RNA and the germline
factor, PRDM14, link X reactivation and stem
cell reprogramming. Mol Cell.
52(6):805-18 (2013).
Our laboratory uses X-chromosome inactivation (XCI) as a model to study the structure
Cifuentes-Rojas C, Hernandez AJ, Sarma K, and function of long noncoding RNAs (lncRNA) in epigenetic regulation. Nowhere in the
Lee JT. Regulatory interactions between RNA mammalian genome are the abundance and roles of lncRNA more evident than at the
and polycomb repressive complex 2. Mol X-inactivation center (Xic). This region harbors transcripts that serve as both repressors
Cell. 17;55(2):171-85 (2014). and activators in the regulation of genes on the X-chromosome. Interestingly, until 150
Simon MD, Pinter SF, Fang R, Sarma K, million years ago, the Xic genes were actually coding and functioned in pathways unrelated
Rutenberg-Schoenberg M, Bowman SK, to XCI. The replacement of the Xic with noncoding transcripts suggests that lncRNAs may
Kesner BA, Maier VK, Kingston RE, Lee JT. be uniquely suited to some types of epigenetic processes. Our research indicates that two
High-resolution Xist binding maps reveal such processes are allelic (cis-regulatory) and locus-specific targeting of chromatin factors
two-step spreading during X-chromosome (e.g., Polycomb complexes). In addition to pursuing mechanisms of action at the Xic, we
inactivation. Nature 504(7480):465-9
are extending analysis to lncRNA occurring on a genome-wide scale and developing novel
(2013).
molecular techniques to do so. Our long-term goal is to understand how lncRNAs interact
Sun S, Del Rosario BC, Szanto A, Ogawa with chromatin complexes to achieve locus-specific and temporally specific gene
Y, Jeon Y, Lee JT. Jpx RNA activates Xist by expression patterns.
evicting CTCF. Cell 153(7):1537-51 (2013).
Yildirim E, Kirby JE, Brown DE, Mercier FE,

Sadreyev RI, Scadden DT, Lee JT. Xist RNA is
a potent suppressor of hematologic cancer in
mice. Cell 152(4):727-42. (2013).
Anguera MC, Sadreyev R, Zhang Z, Szanto A,

Payer B, Sheridan SD, Kwok S, Haggarty SJ,
Sur M, Alvarez J, Gimelbrant A, Mitalipova
M, Kirby JE, Lee JT. Molecular signatures
of human induced pluripotent stem cells
highlight sex differences and cancer genes.
Cell Stem Cell 11(1):75-90 (2012).
MGH PATHOLOGY | 12
TRANSLATIONAL ONCOLOGY LABORATORY
Dora Dias-Santagata, PhD, FACMG

Co-Director, Translational Research Laboratory and
Center for Integrated Diagnostics

Department of Pathology
55 Fruit Street, GRJ-1028A
Boston, MA 02114
Phone: 617-724-1261 • Email: ddiassantagata@mgh.harvard.edu
“Molecular characterization of human tumors to identify markers of
McFadden DG*, Dias-Santagata D*, Sadow
PM, Lynch KD, Lubitz C, Donovan SE, Zheng response to targeted therapeutics…”
Z, Le L, Iafrate AJ, Daniels GH. Identification
of oncogenic mutations and gene fusions
in the follicular variant of papillary thyroid
carcinoma. J Clin Endocrinol Metab. 2014.
*equal contribution Targeted cancer therapy requires the rapid and accurate identification of genetic
Nardi V, Sadow PM, Juric D, Zhao D, Cosper abnormalities predictive of therapeutic response. Our lab has established a high-throughput
AK, Bergethon K, Scialabba VL, Batten JM, clinical genotyping platform – SNaPshot – that detects specific mutations in a broad range of
Borger DR, Iafrate AJ, Heist RS, Lawrence human malignancies, and allows for prospective patient selection to the most appropriate
DP, Flaherty KT, Bendell JC, Deschler D, Li targeted treatments. In an effort to expand the scope of therapeutic options available to
Y, Wirth LJ, Dias-Santagata D. Detection each cancer patient, we have improved upon our original platform by the incorporation
of novel actionable genetic changes in
of next generation sequencing technologies, which we continue to develop. Our goal
salivary duct carcinoma helps direct patient
treatment. Clin Cancer Res. is to obtain a more complete tumor genetic fingerprint that includes mutation status,
2013 19(2):480-90. genetic rearrangements and copy number information for a panel of hundreds of cancer
genes. Our current research efforts are focused on the molecular characterization of rare
Nardi V, Song YC, Santamaria-Barria JA, tumor types, which have to date received less comprehensive attention. Our goal is to
Cosper AK, Lam Q, Faber AC, Boland GM,
elucidate the genetic mechanisms underlying development and progression of these rare
Yeap BY, Bergethon K, Scialabba VL, Tsao H,
Settleman J, Ryan DP, Borger DR, Bhan A, malignancies and to uncover novel diagnostic markers and activated pathways that can be
Hoang MP, Iafrate AJ, Cusack JC, Engelman targeted by currently available therapeutics. Our work led to the identification of clinically-
JA, Dias-Santagata D. Activation of PI3K relevant genetic alterations that may be amenable to therapeutic intervention in Merkel
signaling in Merkel cell carcinoma. cell carcinoma, pleomorphic xanthoastrocytoma and salivary duct carcinoma. We have also
Clin Cancer Res. 2012 18(5):1227-36. developed extensive research collaborations with the MGH Thoracic Oncology and Endocrine
Sequist LV, Heist RS, Shaw AT, Fidias P, Tumor teams, to uncover novel genetic drivers of disease and mechanism of acquired
Rosovsky R, Temel JS, Lennes IT, Digumarthy resistance to therapy.
S, Waltman BA, Bast E, Tammireddy S,
Morrissey L, Muzikansky A, Goldberg SB,
Gainor J, Channick CL, Wain JC, Gaissert
H, Donahue DM, Muniappan A, Wright C,
Willers H, Mathisen DJ, Choi NC, Baselga
J, Lynch TJ, Ellisen LW, Mino-Kenudson M,
Lanuti M, Borger DR, Iafrate AJ, Engelman JA,
Dias-Santagata D. Implementing Multiplexed
Genotyping of Non-Small Cell Lung Cancers
into Routine Clinical Practice. Ann Oncol.
2011.
Dias-Santagata D, Akhavanfard S, David

SS, Vernovsky K, Kuhlmann G, Boisvert SL,
Stubbs H, McDermott U, Settleman J, Kwak
EL, Clark JW, Isakoff SJ, Sequist LV, Engelman
JA, Lynch TJ, Haber DA, Louis DN, Ellisen
LW, Borger DR, Iafrate AJ. Rapid targeted
mutational analysis of human tumors: a
clinical platform to guide personalized cancer
medicine. EMBO Mol Med. 2010 2(5):146-58.
13 | MGH PATHOLOGY
TRANSLATIONAL ONCOLOGY LABORATORY
Long Phi Le, MD, PhD

Assistant Pathologist, Massachusetts General Hospital
Center for Integrated Diagnostics

Charlestown MA 02129
Zheng Z, Liebers M, Zhelyazkova B, Cao Y, “Enabling clinical next-generation sequencing…”
Panditi D, Chen J, Robinson HE, Shim HS,
Chmielecki J, Pao W, Engelman JA, Iafrate
AJ, Le LP. Anchored multiplex PCR for
targeted next-generation sequencing.
Nat Med (in press).
Cancer genetics has expanded significantly in recent years due to various parallel efforts in
Dienstmann R, Dong F, Borger D, Dias-
Santagata D, Ellisen LW, Le LP, Iafrate cancer genotyping by next-generation sequencing. At the same time, targeted therapies have
AJ. Standardized decision support in next also advanced and require identification of molecular signatures to predict their response.
generation sequencing reports of somatic Translating recent discoveries into clinical practice for patient management depends on two
cancer variants. Mol Oncol. 2014 Apr 4. pii: key challenges: implementing high-throughput cancer genotyping at the clinical level and
S1574-7891(14)00069-6. establishing the informatics framework to support clinical implementation of these high-
Gala MK, Mizukami Y, Le LP, Moriichi throughput technologies.
K, Austin T, Yamamoto M, Lauwers GY,
Bardeesy N, Chung DC. Germline mutations Our clinical molecular diagnostic laboratory has implemented a custom next-generation
in oncogene-induced senescence pathways approach based on our own target enrichment method called anchored multiplex PCR (AMP).
are associated with multiple sessile serrated We have applied AMP to detect single nucleotide variants, indels, copy number changes, and
adenomas. Gastroenterology. 2014
fusion transcripts for solid tumors and hematopoietic malignancies. In addition, we are using
Feb;146(2):520-9.
hybridization-based capture technology to profile tumors across a broad range of genes.
Le LP, Dias-Santagata D, Pawlak AC, Cosper
AK, Nguyen AT, Selim MA, Deng A, Horick To support our clinical next-generation sequencing operation, we have developed custom
NK, Iafrate AJ, Mihm MC Jr, Hoang MP. bioinformatics tools for indel, fusion, and copy number detection. Streamlining the clinical
Apocrine-eccrine carcinomas: molecular and
next-generation sequencing operation requires an end-to-end solution. We have employed
immunohistochemical analyses. PLoS One.
2012;7(10):e47290. modern web technologies to create a suite of laboratory tools: molecular laboratory
information management system (LIMS), interface for dynamic variant review, variant
Ryan RJ, Nitta M, Borger D, Zukerberg LR, curation knowledge base, and dynamic clinical reporting interface. We are currently
Ferry JA, Harris NL, Iafrate AJ, Bernstein developing an informatics environment to integrate clinical information with our genomics
BE, Sohani AR, Le LP. EZH2 codon 641
data to derive new genotype-phenotype associations and enable clinical decision support.
mutations are common in BCL2-rearranged
germinal center B cell lymphomas. PLoS One. Our efforts will drive not only the clinical operation but also research and discovery.
2011;6(12):e28585.
MGH PATHOLOGY | 14
EXPERIMENTAL PATHOLOGY UNIT
Frederic I. Preffer, PhD


Simches Building, Room 4-226
Boston, MA 02144
Phone: 617-726-7481 • Fax: 617-724-3164
Email: fpreffer@partners.org
“Elucidating the immunophenotype and functional capacity of stem cells
Preffer F, Dombkowski D. Advances in
complex multiparameter flow cytometry capable of developing into various tissue lineages...”
technology: Applications in stem cell
research. Cytometry B Clin Cytom 2009;
76:295-314.
Dzik WH, Cserti-Gazdewich C, Ssewanyana The common lymphoid progenitor (CLP) responsible for the formation of T, B and NK
I, DeLelys M, Preffer FI. When monocytes cells is derived from a hematopoietic stem cell that is first identified in the embryonic
and platelets compete: the effect of platelet aorto-gonad-mesonephros, a descendent of the mesoderm. The signals to initiate and
count on the flow cytometric measurement regulate development are due to the control imposed by a variety of marrow stromal cells,
of monocyte CD36. Cytometry B Clin Cytom transcription factors, and coordinated regulation by the nervous system, extracellular
2010; 78:81-87.
matrix, cytokines and adipocytes found in the bone marrow microenvironment. The general
Cannizzo E, Bellio E, Sohani AR, Hasserjian consensus of the ontological steps leading to production of naïve B-cells is summarized as
RP, Ferry JA, Dorn ME, Sadowski C, Bucci follows; the earliest identifiable committed B-cells derived from the CLP are called progenitor
JJ, Carulli G, Preffer FI. Multiparameter (Pro) B-cells. Pro B-cells arise after obligate stimulation by the transcription factor PAX-5,
immunophenotyping by flow cytometry in which engenders CD19 production. These CD34+ CD19+ CD10+ CD38+ TdT+ expressing cells
multiple myeloma: the diagnostic utility
lack the pre B-cell receptor or surface immunoglobulin (Ig) and initiate VDJ heavy chain
of defining ranges of normal antigenic
expression in comparison to histology. rearrangements independent of any antigenic exposure. Pro B cells differentiate into CD34-
Cytometry B Clin Cytom 2010; 78B:231-238. CD19+ CD10+ CD38+ TdT- precursor (Pre) B-cells that acquire cytoplasmic and then surface
mu heavy chain with a transient surrogate immunoglobulin light chain. Next, a CD19+ CD10-
Hansen P, Barry D, Restell A, Sylvia D, CD38- immature B-cell expresses surface IgM+ and physiologic light chain. Ultimately, CD19+
Magnin O, Dombkowski D, Preffer F. Physics
of a rapid CD4 lymphocyte count with
CD20+ B-cells co-expressing IgM and IgD heavy chains exit the bone marrow as transitional
colloidal gold. Cytometry A 2012; B-cells and home to secondary lymphoid organs as naive B-cells.
81:222-231.
We are interested in the use of probability state modeling to quantify the locations of
Cannizzo E, Carulli G, Del Vecchio L, antigen modulations during the ontological development of human B-cells to determine the
Ottaviano V, Bellio E, Zenari E, Azzara A,
Petrini M, Preffer F. The role of CD19 and
discrete progenitor and B-cell stages that occur during normal maturation. We will use this
CD27 in the diagnosis of multiple myeloma information to study and predict minimal residual disease in patients with B- lymphoblastic
by flow cytometry: a new statistical model. lymphoma.
Am J Clin. Pathol. 2012; 137:377-386.
The MGH Flow Cytometry research laboratories are located on the MGH campus in Simches
Hansen P, Sylvia D, DeLelys ME, Preffer FI.
The total lymphocyte count is a factor when 3.434 and CNY-5 [2015]. These hospital core resources will entertain research collaborations
using the CD4 count to guide HIV therapy. from throughout the pathology laboratories and greater hospital and university. The CNY
Journal of AIDS and Clinical Research flow laboratory, overseen by Dr. R. Mylvaganam and C. Luo, contains a FACSAria II sorter,
2013 4 http://dx.doi.org/10.4172/2155- LSR-2, Fortessa and FACSFusion sorter for BSL2+ operations. The Simches flow and imaging
6113.1000205. laboratory contains a DiVa cell sorter and LSR-2 operated by D. Dombkowski. In 2015 a
FACSFusion will permit BSL2+ sorting in that facility. This laboratory also contains an Amnis
ISX mkII imaging flow cytometer which permits bright-field and fluorescent visual analysis
of immunophenotyped cells, run by S. Mordecai. The clinical flow cytometry laboratory is
located on Warren 5 on the MGH campus in Boston. Two FACSCanto-IIs are available at
that site.
15 | MGH PATHOLOGY
EXPERIMENTAL PATHOLOGY UNIT
James R. Stone, MD, PhD

Head of Cardiovascular Pathology and
Director of Autopsy Pathology, Massachusetts General Hospital
Simches Research Building, Rm 8236

185 Cambridge Street, CPZN
Boston, MA 02114
Phone: 617-726-8303 • Fax: 617-643-3566 • Email: jrstone@partners.org
Wang H, Albadawi H, Siddiquee Z, Stone “Investigating the molecular mechanisms of vascular disease...”
JM, Panchenko MP, Watkins MT, Stone JR.
Altered vascular activation due to deficiency
of the NADPH oxidase component p22phox.
Cardiovasc. Pathol. 2014; 23:35-42.
Wang H, Smith RN, Spooner AE, Isselbacher The Stone Laboratory studies mechanisms underlying human vascular diseases, such as
EM, Cambria RP, MacGillivray TE, Stone JH, atherosclerosis and vasculitis. Atherosclerosis is the principal cause of heart disease and
Stone JR. Giant cell aortitis of the ascending a leading cause of stroke, making it the most common cause of death in the U.S. The
aorta without signs or symptoms of systemic laboratory is seeking to understand the molecular processes resulting in atherosclerosis in
vasculitis is associated with elevated risk of order to combat this pervasive disease. Atherosclerosis is characterized by the development
distal aortic events. Arthrit. Rheum. 2012;
of necrotic/lipid cores within the intima of arteries at particular sites in the circulation.
64:317-319.
These necrotic/lipid cores form in the setting of a pre-existing intimal hyperplasia,
Siddiquee Z, Zane NA, Smith RN, Stone JR. characterized by the proliferation of smooth muscle-like cells in the intima. The laboratory
Dense IgG4 plasma cell infiltrates associated is investigating both the signal transduction mechanisms responsible for the formation of
with chronic infectious aortitis: implications the preatherosclerotic intimal hyperplasia as well as the factors stimulating the formation of
for the diagnosis of IgG4-related disease.
intimal necrotic/lipid cores.
Cardiovasc. Pathol. 2012; 21:470-475.
Panchenko MP, Siddiquee Z, Dombkowski Essentially all risk factors for atherosclerosis result in the enhanced generation of hydrogen
DM, Alekseyev YO, Lenburg ME, Walker peroxide in the vessel wall by the activation of membrane bound NADPH oxidases. These
JD, MacGillivray TE, Preffer FI, Stone JR. low physiologic levels of hydrogen peroxide are mitogenic, stimulating vascular cell growth
Protein kinase CK1aLS promotes vascular cell
and proliferation. The mechanisms by which low endogenous levels of hydrogen peroxide
proliferation and intimal hyperplasia. Am. J.
Pathol. 2010; 177:1562-1572. stimulate cellular proliferation are currently poorly understood. The laboratory is using
molecular approaches with cultured vascular cells and cultured human arteries to identify
Panchenko MP, Silva N, Stone JR. signal transduction pathways activated by low physiologic levels of hydrogen peroxide. One
Upregulation of a hydrogen peroxide such novel pathway identified in the laboratory is the CK1aLS /hnRNP-C signaling pathway,
responsive pre-mRNA binding protein in
atherosclerosis and intimal hyperplasia.
which has been shown to mediate hydrogen peroxide-stimulated mitogenic signaling in
Cardiovasc. Pathol. 2009; 18: 167-172. vascular cells and to promote intimal hyperplasia in cultured human arteries.
Talusan P, Bedri S, Yang S, Kattapuram T, Intimal hyperplasia, the precursor lesion for atherosclerosis, forms both in vessels that are
Silva N, Roughley PJ, Stone JR. Analysis of prone to develop atherosclerosis and in vessels remarkably resistant to atherosclerosis. Intimal
intimal proteoglycans in atherosclerosis-
prone and atherosclerosis-resistant human hyperplasia can be formed in vitro with human artery segments in culture. The laboratory
arteries by mass spectrometry. Mol. Cell. is using novel human artery culture models combined with molecular analyses of diseased
Proteomics 2005; 4:1350-1357. human arteries to identify, characterize, and functionally assess the vascular wall factors that
promote the transition from intimal hyperplasia to human atherosclerosis.
MGH PATHOLOGY | 16
IMMUNOPATHOLOGY RESEARCH UNIT
Robert B. Colvin, MD
Benjamin Castleman Distinguished Professor of Pathology,
Harvard Medical School (Formerly Chief of Pathology, 1991-2006)
Immunopathology Research Laboratory

Thier Building 8th Floor
Boston MA 02114
Phone: 617-724-3631 • Fax: 617-724-5833
Email: rbcolvin@partners.org
Miyajima M, Chase CM, Alessandrini A, “Pathogenesis of rejection and acceptance of organ transplants...”
Farkash EA, Della Pelle P, Benichou G,
Graham JA, Madsen JC, Russell PS, Colvin
RB. Early acceptance of renal allografts in
mice is dependent on Foxp3+ cells,
Am J Pathol, 178:1635-45, 2011.
The mechanisms of graft acceptance (tolerance) have been a major area of investigation in
Akiyoshi T, Hirohashi T, Alessandrini A, the transplant group at MGH, with mouse, pigs, non-human primates and most recently a
Chase CM, Farkash EA, Neal Smith R, clinical trial. Dr. Colvin has recently studied the events of graft acceptance and the role of
Madsen JC, Russell PS, Colvin RB. Role Foxp3+ Treg cells in mouse kidney allografts. These studies have revealed a novel Treg-rich
of complement and NK cells in antibody organized lymphoid structure (TOLS) in accepted allografts that surround small arteries.
mediated rejection. Hum Immunol. 2012,
Depletion of Treg causes dissolution of the TOLS and precipitates acute graft rejection.
12):1226-32.
Further studies have revealed that mixed chimerism leads to both deletional tolerance to
Hirohashi T, Chase CM, Della Pelle P, MHC antigens and regulatory tolerance to non-MHC antigens.
Sebastian D, Alessandrini A, Madsen JC,
Russell PS, Colvin RB. A novel pathway In studies in human kidney allografts Dr. Colvin’s group was the first to describe chronic
of chronic allograft rejection mediated
antibody mediated rejection, now recognized as the most common cause of late graft
by NK cells and alloantibody, Am
Transplant,12:313-21, 2012. dysfunction. He has shown that deposition of the classical complement component, C4d, in
peritubular capillaries is a useful marker of acute and chronic antibody mediated rejection.
Kawai T, Sachs DH, Sprangers B, Spitzer C4d is the most specific marker of these conditions. Through the efforts of Dr. Colvin
TR, Saidman SL, Zorn E, Tolkoff-Rubin N, and others, new categories of acute and chronic antibody mediated rejection have been
Preffer F, Crisalli K, Gao B, Wong W, Morris
incorporated into the Banff criteria and have become the standard of care. Protocol biopsies
H, LoCascio SA, Sayre P, Shonts B, Williams
WW Jr, Smith RN, Colvin RB, Sykes M, from non-human primate studies have demonstrated sequential stages of chronic humoral
Cosimi AB.Long-term results in recipients of rejection. Dr. Colvin leads the pathology core for several NIH and industry-sponsored clinical
combined HLA-mismatched kidney and bone trials as well as an international NIH genomics project in renal allograft.
marrow transplantation without maintenance
immunosuppression. Am J Transplant. 2014, A major problem in long-term organ grafts is the development of a chronic arteriopathy,
14:1599-611.
which has an unknown pathogenesis. Dr. Colvin and Dr. Paul Russell developed and
Farris AB, Chan S, Climenhaga J, Adam B, characterized a model of the disease, using heart grafts in mice. Coronary arteries develop
Bellamy CO, Serón D, Colvin RB, Reeve J, florid lesions over 4-8 weeks, resembling closely the lesions in human organ grafts. The
Mengel M.Banff fibrosis study: multicenter group showed that chronic allograft arteriopathy can be produced by three distinct immune
visual assessment and computerized analysis pathways, humoral antibody (passive transfer of anti-donor antibodies into RAG-1 knockout
of interstitial fibrosis in kidney biopsies. Am J
mice), T cells (male to female grafts) or natural killer cells (parental graft to F1 recipients).
Transplant. 2014, 14:897-907.
Such antibodies can mediate chronic arteriopathy in the absence of complement, through an
NK cell dependent FcR mechanism.
17 | MGH PATHOLOGY
IMMUNOPATHOLOGY RESEARCH UNIT
Rex Neal Smith, MD, PhD

Pathology Service
55 Fruit Street
Boston, MA 02140
Phone: 617-726-1835 • Fax: 617-726-2365
Email: rnsmith@partners.org
Roth, AJ, Brown, MC, Smith, RN, A.K. “Investigating the causes of acute and chronic rejection...”
Badhwar, AK, Parente, O,. Chung, HC,
Bunch, DO, McGregor, JG, Hogan, SL,
Hu, Y, Yang, JJ, Berg, EA, Niles, J,
Jennette, JC, Preston, GA, and Falk, RJ.
Anti-LAMP-2 Antibodies Are Not Prevalent
Dr. Smith’s research focuses primarily on the immunology of transplantation, with emphasis
in Patients With Antineutrophil Cytoplasmic
Autoantibody Glomerulonephritis. on the transplantation pathology of the heart, kidney, and pancreatic islets. He is particularly
J Am Soc Nephrol, 2012; 23(3):545-555. interested in how the acute and chronic rejection of allografts and xenografts come about.
Studies involve patients and animal experimentation with heart, kidney and pancreatic islet
Wang, H., Smith, R.N., Spooner, AE, grafts. With expertise in these areas, Dr. Smith is a consultant pathologist to investigators
Isselbacher, EM, Cambria, RP, MacGillivray,
within Harvard community, national consortia, and the Transplant Biology Research Program
RE, Stone, JH, and Stone, JR. Giant cell
aortitis of the ascending aorta without at MGH with clinical and preclinical transplant programs. Dr. Smith is also a consultant to
signs or symptoms of systemic vasculitis is revisions of the classification scheme for human heart allograft biopsies.
associated with elevated risk of distal aortic
events. Arthritis Rheum. 2012; 1: 317-319. Current emphasis and ongoing work includes studies of cellular and humoral rejection in
cardiac allografts of humans and mice (hearts) and in kidneys of monkeys and humans.
Herlitz, L.C., Bomback, A.S.. Markowitz,
G.S., Stokes, M.B., Smith, R.N., Colvin, R.B., Dr. Smith has been able to correlate by indirect immunofluorescence C4d staining and the
Appel, G.B., and D’Agati, V.D. Pathology presence of alloantibodies in cardiac allografts. With investigators at other institutions, using
after Eculizumab in Dense Deposit Disease clinical data, criteria are being established for the diagnosis of acute antibody-mediated
and C3 GN. Journal of the American Society rejection in human cardiac transplants. Dr. Smith and Dr. Colvin are studying the progression
of Nephrology: JASN, 2012; 23:1229-1237. of monkey kidney allograft rejection that comes about with development of alloantibodies,
Smith, R.N., Malik, F., Goes, N., Farris, A.B., chronic antibody-mediated rejection. They have been able to establish that alloantibodies
Zorn, E., Saidman, S., Tolkoff-Rubin, N., are the causative of the glomerulopathy of chronic humoral rejection in allografted kidneys,
Puri, S., and Wong, W. Partial Therapeutic and established that chronic antibody-mediated rejection develops through four stages.
Response to Rituximab for the Treatment of Dr. Smith, along with other investigators studying islet allograft survival, has established that
Chronic Alloantibody Mediated Rejection of portal vein-based islet allografts can undergo a non-immunological senescence. Dr. R. Abdi
Kidney Allograft. Transplant Immunology,
and Dr. Smith are investigating why knockout of certain chemokine genes, dendritic cells,
2012; 27(2-3):107-13.
and stem cells affect graft rejection and donor dendritic cell migration. In some autologous
Nadazdin, O., S. Boskovic, S.L. Wee, H. stem cell transplants in mice, sarcomas developed. With AB Collins and Dr. JR Stone we have
Sogawa, I. Koyama, R.B. Colvin, R.N. Smith, established the utility of immunofluorescence for the classification of amyloid deposits. With
G. Tocco, D.H. O’Connor, J.A. Karl, J.C. Dr. M. Soares investigations are ongoing into the mechanism of cerebral malaria. New work
Madsen, D.H. Sachs, T. Kawai, A.B. Cosimi,
with Dr. E. Zorn and J Fraser seeks to identify new alloantibodies in graft rejection by novel
and G. Benichou. Contributions of direct and
indirect alloresponses to chronic rejection of proteomic approaches.
kidney allografts in nonhuman primates.
J Immunol., 2011; 187:4589-4597.
Primo VC, Marusic S, Franklin CC, Goldman

WH, Achaval CG, Smith RN, Arnaout MA,
Nikolic B. Anti-PR3 immune responses
induce segmental and necrotizing
glomerulonephritis. Clinical and Experimental
Immunology, 2010; 159: 327.
MGH PATHOLOGY | 18
PATHOLOGY IMAGING
Yukako Yagi, PhD

Assistant Pathologist in Pathology Informatics
Affiliated Faculty, Wellman Center for Photomedicine
Director of the MGH Pathology Imaging & Communication Technology (PICT) Center

101 Merrimac St. Suite 854
Boston, MA 02114
Phone: 617-643-5162 • Email: yyagi@partners.org
Web: http://www.massgeneral.org/pathology/research/researchlab.aspx?id=1299
“Digital imaging management, expression microdissection and
Yagi Y. Color standardization and
optimization in whole slide imaging. multimodality data analysis”
Diagnostic Pathology 2011, 6(Suppl 1):S15.
Yoo H, Kang D, Katz AJ, Lauwers GY,

Nishioka NS, Yagi Y, Tanpowpong P, Namati
J, Bouma BE, Tearney GJ. Reflectance The MGH Pathology Imaging & Communication Technology (PICT) Center is one of the
confocal microscopy for the diagnosis of best-equipped pathology imaging laboratories in the world. It has a variety of state-of-
eosinophilic esophagitis: a pilot study the-art microscopic, whole slide imaging systems, as well as powerful computational and
conducted on biopsy specimens. Gastrointest storage systems for images and image-based pathology research. The facility has two major
Endosc 2011; 74(5): 992-1000. components: Automated Histology Lab Development and Advanced Pathology Imaging.
Lee RE, McClintock DS, Laver NM, Yagi Y.
Evaluation and optimization for liquid-based Automated Histology Lab Development:
preparation cytology in whole slide imaging. Working with the Department of Pathology’s Clinical Histology Lab, we have been
J Pathol Inform. 2011; 2:46. developing automated and semi-automated histology procedures, demonstrating their
Brachtel E, Yagi Y. Digital imaging in value and identifying the requirements for implementation. Some of the technologies being
pathology - current applications and developed include 1) Automated Tissue Sectioning System, 2) Automated High Volume Ultra
challenges. J Biophotonics. 2012; 5(4): Speed Slide Digitization, 3) Network and Data management for Automated Histology Lab
327-355. and 4) RFID Based Asset Identification and Integration.
Hashimoto N, Bautista, PA, Yamaguchi M,
Ohyama N, Yagi Y, Referenceless image Advanced Pathology Imaging:
quality evaluation for whole slide imaging. Imaging Research includes slide quality, image acquisition, image quality control, spectral
Journal of Pathology Informatics 2012; 3:9. imaging, multi-slide three-dimensional histology reconstruction and human interfaces. The
missions are to improve image quality to improve accuracy of image analysis and computer
Levy BP, Hipp JD, Balis UJ, Yagi Y. Potential
aided diagnosis to support pathologists.
Applications of Digital Pathology and Image
Analysis for Forensic Pathology. Academic
Forensic Pathology 2012; 2(1):74-79. Pathology Imaging Application Development:
1) 3-D Whole Slide Imaging: We seek to understand more detail of histology structure in
2 dimensions and correlate images from other modalities. 3-D image is constructed with
over 100 high-resolution whole-slide images.
2) Multispectral Imaging applications, including multispectral imaging data of WSI. Early
studies have shown the possibility of digital stains such as Digital Trichrome.
3) Cancer Diagnosis Assist System, Automated Fat Analysis in Liver disease.
4) S upporting pathology in developing countries and establishing International
collaborations.
19 | MGH PATHOLOGY
PATHOLOGY IMAGING
Guillermo J. Tearney, MD, PhD, FACC, FCAP

Mike and Sue Hazard Family Research Scholar and Pathologist,
Physicist, Massachusetts General Hospital
Faculty, Wellman Center for Photomedicine

55 Fruit Street, BHX604A • Boston, MA 02114
Phone: 617-724-2979 • Fax: 617-726-4103
Email: gtearney@partners.org • www.tearneylab.org
“The development and validation of non-invasive, high-resolution
Yoo H, Kim JW, Shishkov M, Namati E, Morse
T, Shubochkin R, McCarthy J, Ntziachristos optical methods for disease diagnosis...”
V, Bouma B, Jaffer F, Tearney G. Intra-arterial
catheter for simultaneous microstructural
and molecular imaging in vivo. Nature
Medicine 17: 1680-4 (2012).
Dr. Tearney’s research interests are focused on the development and clinical validation of
Liu L, Gardecki JA, Nadkarni SK, Toussaint non-invasive, high-resolution optical imaging methods for disease diagnosis. Dr. Tearney’s
JD, Yagi Y, Bouma BE, et al. Imaging the lab was the first to perform human imaging in the coronary arteries and gastrointestinal
subcellular structure of human coronary tract in vivo with Optical Coherence Tomography (OCT), which provides cross-sectional
atherosclerosis using micro-optical coherence images of tissue architectural microstructure at a resolution of 10 µm. He has also conducted
tomography. Nature Medicine 17:1010-1014
many of the seminal studies validating OCT and is considered an expert on OCT image
(2011).
interpretation. Recently, Dr. Tearney’s lab has invented a next generation OCT technology,
Yelin D, Rizvi I, White W, Motz J, Hasan T, termed µOCT, which has a resolution of 1 µm and is capable of imaging cells and sub cellular
Bouma BE, Tearney GJ. Three-dimensional structures in the coronary wall. Dr. Tearney has also developed several other technologies,
miniature endoscopy. Nature 443:765 including a confocal endomicroscope capable of imaging the entire esophagus, a capsule
(2006).
that once swallowed captures three-dimensional microscopic images of the GI tract, an
ultraminiature three-dimensional endoscope, a highly efficient form of near field scanning
optical microscopy (NSOM), and novel fluorescence spectroscopy and multimodality imaging
techniques. He has an active program in Raman spectroscopy and has conducted the first
intracoronary Raman in vivo. Dr. Tearney is co-editor of The Handbook of Optical Coherence
Tomography and has written over 200 peer-reviewed publications.
Dr. Tearney’s work extends beyond his laboratory at MGH. Many of his technologies are
being produced commercially, he is the vice-chair of CAP’s in vivo microscope committee
and he has founded the International Working Group on Intravascular OCT Standardization
and Validation, a group that is dedicated to establishing standards to ensure the widespread
adoption of this imaging technology.
MGH PATHOLOGY | 20
MASSGENERAL INSTITUTE FOR NEURODEGENERATIVE DISEASES
Matthew P. Frosch, MD, PhD

Lawrence J. Henderson Associate Professor of Pathology and
Health Sciences & Technology, Harvard Medical School
Director, C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital
MassGeneral Institute for Neurodegenerative Diseases (MIND)
MassGeneral Institute for Neurodegenerative Diseases (MIND)

114 16th Street, Room 2700
Phone: 617-726-5156 • Fax: 617-724-1813
Email: mfrosch@partners.org
Augustinack JC, van der Kouwe AJ, Salat DH,
Benner T, Stevens AA, Annese J, Fischl B,
Frosch MP, Corkin S. H.M.’s contributions to
neuroscience: A review and autopsy studies.
“Development and characterization of animal models of human
Hippocampus. 2014 Aug 25. neurodegenerative diseases...”
Kay KR, Smith C, Wright AK, Serrano-Pozo
A, Pooler AM, Koffie R, Bastin ME, Bak
TH, Abrahams S, Kopeikina KJ, McGuone
D, Frosch MP, Gillingwater TH, Hyman BT, My lab aims to understand cerebral amyloid angiopathy (CAA), using mouse models and
Spires-Jones TL. Studying synapses in human human tissue. In this disease, the peptide Aß deposits in the walls of blood vessels and is
brain with array tomography and electron associated with risk of hemorrhage (‘lobar hemorrhages’). This peptide is the same material
microscopy. Nat Protoc. 2013;8(7):1366-80. that forms the plaques of Alzheimer disease, and nearly all patients with Alzheimer disease
Arbel-Ornath M, Hudry E, Eikermann-Haerter have pathologic evidence of CAA as well. CAA also occurs in the absence of histologic
K, Hou S, Gregory JL, Zhao L, Betensky evidence of Alzheimer disease, and can present with hemorrhages or with cognitive changes.
RA, Frosch MP, Greenberg SM, Bacskai In clinicopathologic studies, we have found that this latter presentation is associated with the
BJ. Interstitial fluid drainage is impaired in presence of an inflammatory response, often containing giant cells. This subset of patients
ischemic stroke and Alzheimer’s disease can have dramatic recoveries of cognitive function after immunosuppressive therapy.
mouse models. Acta Neuropathol. 2013
Sep;126(3):353-64.
We are interested in the sequence of events by which Aß is deposited in blood vessels, what
Serrano-Pozo A, Qian J, Monsell SE, Frosch factors determine the distribution of involvement, what the consequences are for the cells
MP, Betensky RA, Hyman BT. Examination of the vessel and how this material can respond to therapeutic interventions that have been
of the clinicopathologic continuum of shown to alter Aß deposits in the brain (immunotherapy, gamma-secretase inhibitors).
Alzheimer disease in the autopsy cohort Current topics of particular interest involve the timing of oxidative stress induction by
of the National Alzheimer Coordinating
CAA, expression of matrix degrading enzymes such as MMP-9 and induction of apoptosis
Center. J Neuropathol Exp Neurol. 2013
Dec;72(12):1182-92. in vascular smooth muscle cells. We use serial in vivo multiphoton imaging with specific
probes for these various processes and link the spatial and temporal distribution of the
Serrano-Pozo A, Qian J, Monsell SE, Blacker pathologic changes with the development of CAA. We complement these studies with
D, Gómez-Isla T, Betensky RA, Growdon JH, immunohistochemistry, image reconstruction and laser capture microdissection to define
Johnson KA, Frosch MP, Sperling RA, Hyman
alterations in gene expression that occur in smooth muscle cells in the proximity of amyloid
BT. Mild to moderate Alzheimer dementia
with insufficient neuropathological changes. deposits of CAA. Finally, our observations in mouse models of CAA can be validated through
Ann Neurol. 2014 Apr;75(4):597-601. the use of human autopsy tissue, collected through the Massachusetts Alzheimer Disease
Research Center Neuropathology Core.
I also work with a range of collaborators to understand the relationship between

neuropathologic findings in the setting of disease – including Alzheimer disease, Parkinson
disease, Amyotrophic Lateral Sclerosis and others – and other biochemical or functional
markers of disease. These studies include advancing imaging methods (DTI, OCT and others)
as well as various genetic studies (deep sequencing as well as GWAS), cell biology and
structural biology.
21 | MGH PATHOLOGY
CENTER FOR CANCER RESEARCH
Gad A. Getz, PhD

Director of Bioinformatics, Massachusetts General Hospital Cancer Center and
Department of Pathology
Paul C. Zamecnik Chair of Oncology, Massachusetts General Hospital Cancer Center
Director, Cancer Genome Computational Analysis and Associate Member,
Broad Institute
Massachusetts General Hospital Cancer Center

Charlestown, MA, 02129
Selected Publications Phone: 617-724-7014 • Email: GGETZ1@mgh.harvard.edu
Lawrence MS, Stojanov P, Mermel CH,
Robinson JT, Garraway LA, Golub TR,
Meyerson M, Gabriel SB, Lander ES*, Getz
G*. Discovery and saturation analysis of
“Finding cancer genes and pathways is a crucial first step towards
cancer genes across 21 tumour types. therapy…”
Nature. 2014; 505(7484):495-501.
*Co-corresponding authors
Lawrence MS, et al, Lander ES*, Getz G*.

Mutational heterogeneity in cancer and the The Getz Laboratory is focused on cancer genome analysis which includes two major tasks: (i)
search for new cancer-associated genes. Characterization – cataloging of all genomic events and the mechanisms that created them
Nature. 2013; 499(7457):214-8. during the evolution of the cancer, including events at the DNA, RNA and protein levels in
*Co-corresponding authors normal and tumor samples from an individual patient; and (ii) Interpretation – analysis of the
characterization data across a cohort of patients with the aim of identifying the alterations
Landau DA, Carter SL, Stojanov P, et al,
Brown JR*, Getz G*, Wu CJ*.Evolution in genes and pathways that cause cancer or increase its risk as well as identifying molecular
and impact of subclonal mutations in subtypes of the disease, their markers and relationship to clinical variables.
chronic lymphocytic leukemia. Cell. 2013;
152(4):714-26. *Co-corresponding authors Characterizing the Cancer Genome: Cancer is a disease of the genome that is driven by a
combination of possible germline risk-alleles together with a set of ‘driver’ somatic mutations
Cibulskis K, Lawrence MS, Carter SL,
that are acquired during the clonal expansion of increasingly fitter clones. In order to generate
Sivachenko A, Jaffe D, Sougnez C, Gabriel
S, Meyerson M, Lander ES, Getz G. Sensitive a comprehensive list of all germline and somatic events that occurred during life and the
detection of somatic point mutations in development of the cancer, we are developing and applying highly sensitive and specific tools
impure and heterogeneous cancer samples. for detecting different types of mutations in massively-parallel sequencing data. The volume,
Nat Biotechnol. 2013; 31(3):213-9. noise and complexity of these data require developing computational tools using state-
of-the-art statistical and machine learning approaches to extract the signal from the noise
Carter SL, Cibulskis K, Helman E, McKenna
A, Shen H, Zack T, Laird PW, Onofrio RC, (e.g. MuTect, CapSeg, dRanger, BreakPointer etc.). We are also developing benchmarking
Winckler W, Weir BA, Beroukhim R, Pellman approaches to assess the accuracy of the tools to help guide and interpret the experiments.
D, Levine DA, Lander ES, Meyerson M, Getz
G. Absolute quantification of somatic DNA Detecting Cancer-Associated Genes: Next, we analyze the detected events across a cohort
alterations in human cancer. Nat Biotechnol. of samples searching for genes/pathways that show significant signals of positive selection.
2012; 30(5):413-21. To that end, we construct a statistical model of the background mutational processes and then
Mermel CH, Schumacher SE, Hill B, Meyerson detect genes that deviate from it. As part of constructing the models, we study and infer the
ML, Beroukhim R*, Getz G*. GISTIC2.0 mutational processes that affected the samples (carcinogens, defects in repair mechanisms,
facilitates sensitive and confident localization etc.) and their timing.
of the targets of focal somatic copy-number
alteration in human cancers. Genome Biol. We have developed tools for detecting significantly gained or lost genes in cancer (GISTIC)
2011; 12(4):R41. *Co-corresponding authors and genes with increased density or irregular patterns of mutations (MutSig). We recently
reported the importance of modeling the heterogeneity of these models across patients,
sequence contexts and the genome, when searching for cancer genes. We are continuously
improving these methods and working towards generating a unified approach that integrates
all types of alterations to better detect cancer genes.
Heterogeneity and clonal evolution of cancer: Cancer samples are heterogeneous, containing
a mixture of normal cells and cancer cells that often represents multiple subclones. We are
developing tools (ABSOLUTE) for characterizing the heterogeneity of cancer samples using
copy-number and mutation data measured on bulk samples and now also using single cells.
Using these tools, we can infer which mutations are clonal or sub-clonal, as well as estimate
the number of subclones and their distribution over space and time. We are now working to
introduce these concepts to clinical trials and eventually clinical care.
MGH PATHOLOGY | 22
CENTER FOR SYSTEMS BIOLOGY
John M. Higgins, MD
Assistant Professor of Systems Biology, Harvard Medical School
Center for Systems Biology

Richard B. Simches Research Center
185 Cambridge Street, Room 5.222
Boston, MA 02114
Phone: 617-643-6129 • Fax: 617-643-6133 • Email: jmhiggins@partners.org
“Developing mathematical descriptions of complex human disease
Malka R, Delgado FF, Manalis SR, Higgins
JM. In Vivo Volume and Hemoglobin phenotypes and how they change over time...”
Dynamics of Human Red Blood Cells.
PLoS Computational Biology, 2014, in press.
Wood DK, Soriano AO, Mahadevan L,

Higgins JM, Bhatia SN. A biophysical I study the dynamics of human pathophysiologic processes by developing mathematical
marker of severity in sickle cell disease. descriptions of complex human disease phenotypes and how they change over time. The
Science Translational Medicine, 2012; research combines medical insight, dynamical systems theory, and experiments utilizing
4(123)123ra26. microfluidics, video processing, flow cytometry, simulation, and large-scale analysis of
Higgins JM & Mahadevan, L. Physiological
medical databases in pursuit of two goals: (1) advancing fundamental understanding of
and pathological population dynamics human pathophysiologic process and their dynamics, and (2) improving patient diagnosis,
of circulating human red blood cells. monitoring, and treatment.
Proceedings of the National Academy of
Sciences of the United States of America, Pathophysiology may be described at the molecular, cellular, tissue and organismal levels and
2010; 107:20587-20592. [See commentaries may show clinically significant variation over time scales ranging from less than a second to
in New England Journal of Medicine, 2011;
more than a decade. Using clinical laboratory data and experiments with clinical specimens,
364(4):376-7 and Nature Medicine, 2010;
16(12): 1386]. we can develop detailed descriptions of pathophysiologic states in terms of clinically relevant
and measurable quantities. We can then propose mathematical models describing the
Higgins JM, Eddington DT, Bhatia S, interrelationships between these state variables and how those relationships change when
Mahadevan L. Statistical Dynamics of perturbed by disease. Models must be consistent with both existing basic research and
Flowing Red Blood Cells by Morphological
clinical experience, and once validated will enable the estimation of dynamic parameters.
Image Processing. PLoS Computational
Biology, 2009; 5(2):e1000288. Personalized estimates of parameters often quantify unmeasurable aspects of biological
processes, revealing new insight into pathophysiology and providing opportunities for novel
Higgins JM and Sloan SR. Stochastic approaches to diagnosis and patient monitoring. Recent work has focused on population
Modeling of Human RBC Alloimmunization: dynamics of cell characteristics in anemia and inflammatory states, blood flow in sickle cell
Evidence for a Distinct Population of
Immunologic Responders. Blood, 2008;
disease, and immunologic response to transfusion.
112(6):2546-53. [See Blood editorial
commentary: Blood, 2008; 15;112(2):
2180-1].
Higgins JM, Eddington DT, Bhatia SN,

Mahadevan L. Sickle cell vaso-occlusion and
rescue in a microfluidic device. Proceedings
of the National Academy of Sciences of the
United States of America, 2007; 104:20496-
20500. [See commentary in Science Editors’
Choice: Science, 2007; 318(5857): 1699].
23 | MGH PATHOLOGY
Andrea I. McClatchey, PhD

Principal Investigator, Massachusetts General Hospital Cancer Center
MGH Cancer Center

Phone: 617-726-5648 • Fax: 617-724-6919
Email: mcclatch@helix.mgh.harvard.edu
“The role of the membrane: cytoskeleton interface in receptor tyrosine
Hebert AM, Duboff B, Casaletto JB, Gladden,
AB, McClatchey AI. Merlin/ERM proteins kinase signaling, tissue morphogenesis and tumorigenesis...”
establish cortical asymmetry and centrosome
position. Genes Dev. 26(24): 2709-23, 2012
Dec 15.
Casaletto JB, Saotome I, Curto M, The McClatchey laboratory seeks to understand how cells organize their outer membrane or
McClatchey AI. Ezrin-mediated apical cortex, which, in turn, determines their identity, behavior, and interface with the external
integrity is required for intestinal environment. Cancer cells exhibit defective membrane organization and therefore interact
homeostasis. Proc Natl Acad Sci U S A. inappropriately with other cells and with their environment. Our research stems from a
108(29):11924-9, 2011 Jul 19. longstanding dedication to understanding the molecular basis of neurofibromatosis type 2
Gladden AB, Hebert AM, Schneeberger EE, (NF2), a familial tumor syndrome caused by mutation of the NF2 tumor suppressor gene. The
McClatchey AI. The NF2 tumor suppressor, NF2-encoded protein, Merlin, and closely related ERM proteins (Ezrin, Radixin, and Moesin)
Merlin, regulates epidermal development are key architects of the cell cortex.
through the establishment of a junctional
polarity complex. Dev Cell. 19(5):727-39, Understanding morphogenesis and tumorigenesis
2010 Nov 16.
The vast array of forms and functions exhibited by different cell types is made possible by
Benhamouche S, Curto M, Saotome the organization of specialized domains within the cell cortex such as cell:cell and cell:matrix
I, Gladden AB, Liu CH, Giovannini M, adhesions, the intestinal brush border and immunological synapse. The assembly of such
McClatchey AI. Nf2/Merlin controls cortical domains involves the coordination of processes occurring at the plasma membrane
progenitor homeostasis and tumorigenesis in with those in the underlying cytoskeleton. Cortical protein complexes position membrane
the liver. Genes Dev. 24(16):1718-30, 2010
receptors, control their abundance and activity and link them to the cortical cytoskeleton,
Aug 15.
thereby serving both regulatory and architectural functions. The overarching goal of my
Morris ZS, McClatchey AI. Aberrant epithelial laboratory is to understand how the organization of protein complexes at the cell cortex
morphology and persistent epidermal growth contributes to morphogenesis and tumorigenesis. This stems from our dedication to defining
factor receptor signaling in a mouse model the molecular function of the NF2 protein Merlin, which, like the ERMs, can link membrane
of renal carcinoma. Proc Natl Acad Sci U S A.
106(24):9767-72, 2009 Jun 16.
proteins to the cytoskeleton.
Cole BK, Curto M, Chan AW, McClatchey Through the generation of mouse models, we identified key roles for Merlin/ERMs in
AI. Localization to the cortical cytoskeleton morphogenesis and tumorigenesis in many tissues. Molecular and cell-based studies suggest
is necessary for Nf2/merlin-dependent that these phenotypes are caused by defective distribution of membrane receptors such
epidermal growth factor receptor silencing.
Mol Cell Biol. 28(4):1274-84, 2008 Feb. as EGFR/ErbBs, cell junctions and/or protein complexes that guide the orientation and
function of the mitotic spindle. We also found that a key function of Merlin is to restrict the
distribution of Ezrin. In the absence of Merlin, as in NF2-mutant cancers, unrestricted cortical
Ezrin drives aberrant membrane receptor distribution and defective spindle orientation/
integrity. These studies yield new insight into how the organization of the cell cortex drives
normal cell behavior and how aberrant cortical organization contributes to unscheduled cell
proliferation and tumorigenesis.
Ongoing studies extend basic and translational aspects of this work. A key goal is to define
the molecular mechanism by which Merlin/ERMs organize the cell cortex and control receptor
distribution and spindle orientation/integrity. We are also pursuing translational avenues for
NF2-mutant tumors that stem directly from our basic studies such as targeting aberrant ErbB
signaling or centrosome/spindle function. We believe that the continued partnering of basic
and translational studies will lead to novel therapeutic options for NF2-mutant tumors and
advance our understanding of how these basic cellular activities contribute to other human
cancers.
MGH PATHOLOGY | 24
INFECTIOUS DISEASES
Eric S. Rosenberg, MD
Associate Professor of Medicine, Harvard Medical School
Physician, Massachusetts General Hospital
Director, Clinical Microbiology Laboratory
Infectious Disease Division and Clinical Microbiology Laboratories

55 Fruit Street
Gray J-529
Boston, MA 02114
Phone: 617-724-7519 • Email: erosenberg1@partners.org
“To characterize the mechanisms of CD4 cell dysfunction in persons
CLSI. Criteria for Laboratory Testing and
Diagnosis of HIV Infection; Approved with acute HIV infection...”
Guideline. CLSI document M53-A. Wayne,
PA: Chair holder: Rosenberg, ES. Clinical and
Laboratory Standards Institute; 2011.
Rychert J, Strickt D, Robinson J, Rosenberg In the vast majority of individuals infected with HIV-1, infection is characterized by the
ES. Detection of HIV gp120 in Plasma inability of the immune system to control viral replication. This failure of containment of
during Early HIV Infection is Associated HIV-1 replication inevitably results in disease progression. The one notable exception to this
with Increased Proinfl ammatory and observation is in persons with long-term non-progressive infection who appear to contain
Immunoregulatory Cytokines. AIDS Research viral replication in the absence of antiretroviral therapy. My laboratory investigates the
and Human Retroviruses. Aug 19 (2010).
mechanisms used by the cellular immune system in these individuals whom are successful
Rosenberg ES, Graham BS, Chan ES, in mounting effective responses against HIV-1. Recent work has focused on characterizing
Bosch RJ, Stocker V, Maenza J, Markowitz CD4+ T helper cell function in individuals with long-term non-progressive infection and in
M, Little S, Sax PE, Collier AC, Nabel G, a cohort of persons identified with acute HIV-1 infection prior to antibody seroconversion
Saindon S, Flynn T, Kuritzkes D, Barouch whom when treated also generate functionally relevant immune responses. Currently, we are
DH for the ACTG A5187 Team. Safety
studying immunologic and virologic mechanisms employed by both host and virus that result
and Immunogenicity of Therapeutic DNA
Vaccination in Individuals Treated with in success or failure of the host immune response. In particular, we are studying how HIV-
Antiretroviral Therapy during Acute/Early specifi c CD4+ T helper cell responses are generated and subsequently disarmed during acute
HIV-1 Infection. PLoS ONE 5(5):e10555, HIV-1 infection. In addition, we are studying the immunologic, virologic and clinical impact
(2010). of antiretroviral therapy initiated during acute HIV-1 infection. Further investigation into the
Rosenberg ES, Davidian M, Banks HT. Using
function of CD4+ T helper cells in these individuals will hopefully provide critical insight into
mathematical modeling and control to the pathogenesis of HIV and support rationale for further immunotherapeutic interventions
develop structured treatment interruption and vaccine development.
strategies for HIV infection. Drug and alcohol
dependence 88 Suppl 2:S41-51 (2007).
Kassutto S, Johnston MN, Rosenberg ES.

Incomplete HIV-1 antibody evolution and
sero-reversion in acutely infected individuals
treated with early antiretroviral therapy.
Clinical Infectious Diseases 40(6):868-73
(2005).
Rychert J, Saindon S, Placek S, Daskalakis

D, Rosenberg ES. Sequence Variation Occurs
in CD4 Epitopes During Early HIV Infection.
J Acquir Immune Defic Syndr 46(3):261-7
(2007).
Kaufmann DE, Bailey PM, Sidney J, Wagner

B, Norris PJ, Johnston MN, Cosimi LA, Addo
MM, Lichterfeld M, Altfeld M, Frahm N,
Brander C, Sette A, Walker BD, Rosenberg
ES. Comprehensive Analysis of HIV-1-
Specific CD4 Responses Reveals Marked
Immunodominance of Gag and Nef and the
Presence of Broadly Recognized Peptides.
Journal of Virology 78:4463-4477 (2004).
25 | MGH PATHOLOGY
UROLOGY-PATHOLOGY RESEARCH LABORATORY
Chin-Lee Wu, MD, PhD

Director, Urology Research Laboratory

55 Fruit Street
Warren Building, Room 333A
Boston, MA 02114
Phone: 617-726-8454 • Fax: 617-724-7803 • Email: cwu2@partners.org
“Studying the molecular basis of human urologic tumors, including
Gershman B, Dahl DM, Olumi AF, Young
RH, McDougal WS,Wu C-L. Smaller prostate cancers of the prostate, bladder and kidney...”
gland size and older age predict Gleason
score upgrading. Urol Oncol. 31(7):1033-7
(2013).
Dong F, Wang C, Farris AB, Wu S, Lee H, Our laboratory studies the molecular biomarkers of urologic tumors, including cancers of
Olumi AF, McDougal WS, Young RH, Wu C-L. the prostate, bladder and kidney. The long-term goal of these studies is to develop new
Impact on the Clinical Outcome of Prostate diagnostic methods and therapeutic regiments for these cancers.
Cancer by the 2005 International Society
of Urological Pathology Modified Gleason Prostate cancer is the most common cancer and the second leading cause of cancer death
Grading System. Am J Surg Pathol. 36
of men in the US. We are interested in identifying gene expression profiles associated
(6):838-43 (2012).
with the development, diagnosis and prognosis of prostate cancer. We have used laser
Lu J, Wirth GJ, Wu S, Chen J, Dahl DM, capture microdissection and DNA microarray techniques to identify a group of genes whose
Olumi AF, Young RH, McDougal WS, Wu expression can be used to predict the prostate cancer outcome. We are in the process of
C-L. A Close surgical margin after radical developing a new gene-based diagnostic test to guide clinical management of prostate
prostatectomy is an independent predictor of
cancer. The genes identified by this approach may also be used as new therapeutic targets.
recurrence. J Urololgy. 188(1):91-7 (2012).
Zhong W-D, Liang Y-X, Lin SX, Li L, He Currently, there is a clinical need to improve the method for imaging prostate cancer in
H-C, Bi X-C, Han Z, Dai Q-S, Ye Y-K, Chen vivo. Through collaboration with Dr. Leo Cheng, MGH Pathology and Radiology, we have
Q-B, Wang Y, Zeng G-H, Zhu G, Zhang Z, identified a metabolomic signature of prostate cancer. We are applying this signature in the
Chen Z-N, Wu C-L. Expression of CD147 is
development of an in vivo imaging technique for prostate cancer. The new imaging method
Associated with Prostate Cancer Progression.
Intl J of Cancer. 130:300–308 (2012). may help to detect, localize and quantify prostate cancer in vivo. Most prostate cancer death
is due to the development of androgen independence. Androgen receptor is responsible for
Qin W, Bajaj V, Malinowska I, Lu X, cell growth in both androgen dependent and independent prostate cancers. We identified
Macconaill L, Wu CL*, Kwiatkowski DJ*. two novel androgen receptor co-activators that may be involved in the development of
Angiomyolipoma Have Common Mutations in
androgen independence in prostate cancer. Characterizing these androgen receptor
TSC2 but No Other Common Genetic Events.
PLoS One. 6(9):e24919. (2011) co-activators may lead to new drug targets for androgen independent prostate cancer.
(*equal contribution authors).
Our laboratory is jointly supported by the MGH Urology and Pathology Departments and
Wu C-L, Jordan KW, Ratai EM, Sheng J, the MGH Cancer Center. In addition to our own investigations, we have established
Adkins CB, DeFeo EM, Jenkins BG, Ying
L, McDougal WS, Cheng LL. Metabolomic
productive collaborations with investigators both locally and around the world. We provide
imaging for human prostate cancer clinical, research and technical expertise as well as pathology specimens to these collaborative
detection. Sci. Transl. Med. 2, 16ra8 (2010). studies.
Jiang Z, Chu PG, Woda BA, Rock KL, Liu Q,

Hsieh CC, Li C, Chen W, Duan HO, McDougal
WS and Wu C-L. Analysis of RNAbinding
protein IMP3 to predict metastasis and
prognosis of renal-cell carcinoma: a
retrospective study. Lancet Oncology
(7):556-64 (2006).
MGH PATHOLOGY | 26
KOCH INSTITUTE FOR INTEGRATIVE CANCER RESEARCH AT MIT
Ömer H. Yilmaz, MD PhD

Assistant Professor of Biology
Member, Koch Institute for Integrated Cancer Research
Massachusetts Institute of Technology
77 Massachusetts Avenue, 76-353D

Cambridge MA 02139 USA
Phone: (617) 324-7633 • email: ohyilmaz@mit.edu • website: yilmaz-lab.mit.edu
“The connection between diet, physiology, and stem cells in regeneration
Mihaylova MM, Sabatini DM, and Yilmaz ÖH.
Dietary and Metabolic Control of Stem Cell and cancer…”
Function in Physiology and Disease.
Cell Stem Cell 14(3):292-305 (2014).
Birsoy K, Wang T, Possemato R, Yilmaz ÖH,

Koch CE, Chen WW, Hutchins AW, Gultekin The goal of the Yilmaz laboratory is to understand how diverse diets influence the
Y, Peterson TR, Carette JE, Brummelkamp regeneration and development of cancers in the intestine. Although diet is known to impact
TR, Clish CB, Sabatini DM. MCT1-mediated
the regeneration of the intestine and the incidence of intestinal cancers, very little
transport of a toxic molecule is an effective
strategy for targeting glycolytic tumors. is understood about the cellular and molecular mechanisms that underlie these processes.
Nature Genetics 45(1):104-8 (2013). The intestine is a rapidly proliferating organ that on average replaces its entire lining every
5 days, which in an average adult human equates to approximately 300 grams of new
Yilmaz, Ö.H., Katajisto, P., Lamming, D.W., intestinal tissue being generated daily. Intestinal stem cells power this regeneration by
Gültekin, Y., Bauer-Rowe, K.E., Sengupta,
undergoing either self-renewal divisions that generate more stem cells or a series of divisions
S., Birsoy, K., Durun, A., Yilmaz, V.O., Selig,
M., Nielsen, G.P., Mino-Kenudson, M., that engender the various differentiated cell types of the adult intestine.
Zukerberg, L.R, Bhan, A.K., Deshpande,
V., and Sabatini, D.M. mTORC1 in the To function properly, intestinal stem cells also require support cells, or niche cells, consisting
Paneth cell niche couples intestinal stem- of Paneth cells that play a key role in modulating stem cell function in response to calorie
cell function to calorie intake. Nature intake. By integrating cues from their Paneth cell niche, intestinal stem cells remodel the
486(7404):490-5 (2012).
composition and function of the intestine, allowing for the intestine to dynamically adapt to
Yilmaz, Ö.H., Valdez, R., Thiesen, B.K., different diets. Since stem cells and their niche drive intestinal regeneration in response to
Guo, W. Ferguson, D.O., Wu, H., and diet and because most cancers are understood to arise from transformed or mutated stem
Morrison, S.J. Pten dependence distinguishes cells, it is likely that intestinal stem cells, diet, and cancer are interconnected. The Yilmaz lab
haematopoietic stem cells from leukaemia- is working on elucidating the molecular mechanisms underpinning this connection between
initiating cells. Nature 441: 475-482 (2006).
stem cells, diet, and cancer in conditions of low calorie diets as well as in high fat diet-
induced obesity. By better understanding how intestinal stem cells adapt to diverse diets,
his lab hopes to identify and develop new strategies that prevent and reduce the growth of
cancers involving the intestinal tract that includes the small intestine, colon, and rectum.
27 | MGH PATHOLOGY
Lee Zou, PhD

Associate Scientific Director, Massachusetts General Hospital Cancer Center
The Jim & Ann Orr MGH Research Scholar
MGH Cancer Center

Phone: 617-724-9534 • Fax: 617-726-7808 • Email: lzou1@partners.org
Selected Publications “Understanding the underlying principles of cellular responses to

Wu, C., Ouyang, J., Mori, E., Nguyen, H. D., chromosomal insults and their roles in the maintenance of genomic
Marechal, A., Hallet, A., Chen, D. J., and Zou,
L. (2014) SUMOylation of ATRIP Potentiates stability...”
DNA Damage Signaling by Boosting Multiple
Protein Interactions in the ATR Pathway.
Genes & Dev. 28:1472-84.
Maintenance of genomic integrity is essential for the survival of all organisms. In humans, loss
Marechal, A., Li. J. M., Ji, J., Wu, C., Yazinski, of genomic integrity is closely linked to cancers and other genetic diseases. The genomes of
S. A., Nguyen, H. D., Liu, S., Jimenez, A. E.,
cells are constantly challenged by DNA damage, DNA replication interference, and other forms
Jin, J., and Zou, L. (2014) PRP19 transforms
into a sensor of RPA-ssDNA after DNA of cellular stresses. In response to such stresses, cells activate a complex signaling pathway,
damage and drives ATR activation via a termed the checkpoint, to orchestrate various cellular responses. The checkpoint-mediated
ubiquitin circuitry. Mol. Cell 53:235-246. regulation and coordination of processes such as cell cycle transitions, DNA replication, and
DNA repair are crucial for the stability of the genome. Mutations impairing the function of
Centore, R, C., Yazinski, S. A., Tse, A., and
this signaling pathway have been found to associate with cancer and cancer predisposition
Zou, L. (2012) Spartan/C1orf124, a Reader
of PCNA Ubiquitylation and a Regulator of syndromes (e.g. p53, Brca1, ATM, Chk2, and Nbs1). Furthermore, checkpoint is activated during
UV-Induced DNA Damage Response. Mol. the early stages of human tumorigensis, suggesting a potential role of checkpoint as an anti-
Cell 46:625-635. cancer barrier against the genomic instability induced by oncogenic stress.
Liu, S., Shiotani, B., Lahiri, M., Marechal,
The long-term goal of our research is to understand the underlying principles of cellular
A., Tse, A., C. C. Leung, J. N. M. Glover,
Yang, X. H., and Zou, L. (2011) ATR responses to chromosomal insults and their roles in the maintenance of genomic stability.
Autophosphorylation as a Molecular Switch Currently, our research is focused on three fundamental questions about checkpoint signaling.
for Checkpoint Activation. Mol. Cell 43: First, how is checkpoint activated by DNA damage in cells? Second, how does checkpoint
192-202. transmit DNA damage signals through different types of protein modifications? Third, how
Flynn, R. L., Centore, C. R., O’Sullivan, R.
does checkpoint protect the DNA replication forks encountering DNA damage? To address
J., Rai, R., Tse, A., Songyang, Z., Chang, these questions, we are developing new biochemical and cell biological assays to examine the
S., Karlseder, J., and Zou, L. (2011) TERRA functions of the key checkpoint proteins. The ATR-ATRIP kinase complex is a central player
and hnRNPA1 Orchestrate an RPA-to-POT1 for the checkpoint responses to many types of DNA damage in human cells. We recently
Switch on Telomeric Single-Stranded DNA. found that single-stranded DNA (ssDNA) coated with RPA, a common structure generated at
Nature 471:532-536. DNA damage and stalled replication forks, is the key structure that recruits ATR-ATRIP. Our
biochemical analyses have enabled us to establish an in vitro system recapitulating the initial
steps of checkpoint activation. Using this system, we are systematically investigating how the
checkpoint-signaling complex (so called the “checkosome”) is assembled on RPA-coated ssDNA
and other DNA structures associating with DNA damage. This system will be further explored
to understand how DNA damage sensors initiate checkpoint signaling on DNA, and how DNA
damage signals are relayed to downstream effectors.
MGH PATHOLOGY | 28
Phone: 617-726-5690
Fax: 617-726-5684
Cover Photo:
Confocal microscopic image of a RAS-induced embryonal rhabdomyosarcoma (ERMS) arising in a fluorescent transgenic
zebrafish. Green fluorescent protein expression is confined to the myf5+ ERMS-propagating cells that drive continued tumor
growth and relapse. The nuclei of differentiated tumor cells are labeled with blue fluorescent protein and myosin antibody
(MF20, red). Large-scale chemical genetic approaches have now been developed to kill tumor cells in the zebrafish and to assess
drug effects on heterogeneity within the model. These approaches have identified novel therapeutic strategies that are now
moving toward clinical development.
2014-2015 | Pathology Basic Scientific Research

Phone: 617-726-5690
Fax: 617-726-5684

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2014-2015 | Pathology Basic Scientific Research

Massachusetts General Hospital

TRAINING GRANT LABORATORIES...............................................................................................iii

Molecular Pathology Unit

Howard Hughes Medical Institute

Translational Oncology Laboratory

Experimental Pathology Unit

Immunopathology Research Unit

Pathology Faculty Affiliated With Other Departments

Laboratory-based scientific research is a major component of MGH Pathology, and is complemented

J. Keith Joung, MD, PhD

MGH PATHOLOGY | iii

J. Keith Joung, MD, PhD

Molecular Pathology Unit

Epigenome Editing Using Targeted Transcription Factors

David M. Langenau, PhD

Massachusetts General Hospital

Martin Aryee, PhD

Molecular Pathology Unit

Epigenomic Studies of Complex Disease: Despite the discovery of numerous disease-associated

Atul K. Bhan, MBBS, MD

Massachusetts General Hospital

A. John Iafrate, MD, PhD

Molecular Pathology Unit

Iafrate AJ, Feuk L., Rivera MN, Listewnik

Yip S, Miao J, Cahill DP, Iafrate AJ, Aldape K,

Cahill DP, Levine KK, Betensky RA, Codd PJ,

Molecular Pathology Unit

Rivera MN, Kim WJ, Wells J, Driscoll DR,

Molecular Pathology Unit

Molecular Pathology Unit

Mario L. Suvà, MD, PhD

Molecular Pathology Unit

Bradley Bernstein, MD, PhD

Massachusetts General Hospital

Jeannie T. Lee, MD, PhD

Howard Hughes Medical Institute

Yildirim E, Kirby JE, Brown DE, Mercier FE,

Anguera MC, Sadreyev R, Zhang Z, Szanto A,

Dora Dias-Santagata, PhD, FACMG

Center for Integrated Diagnostics

Dias-Santagata D, Akhavanfard S, David

Long Phi Le, MD, PhD

Center for Integrated Diagnostics

Frederic I. Preffer, PhD

Massachusetts General Hospital

James R. Stone, MD, PhD

Simches Research Building, Rm 8236

Immunopathology Research Laboratory

Rex Neal Smith, MD, PhD

Primo VC, Marusic S, Franklin CC, Goldman

Yukako Yagi, PhD

Massachusetts General Hospital

Yoo H, Kang D, Katz AJ, Lauwers GY,

Guillermo J. Tearney, MD, PhD, FACC, FCAP

Massachusetts General Hospital

Matthew P. Frosch, MD, PhD

MassGeneral Institute for Neurodegenerative Diseases (MIND)

I also work with a range of collaborators to understand the relationship between

Gad A. Getz, PhD

Massachusetts General Hospital Cancer Center

Lawrence MS, et al, Lander ES*, Getz G*.

Center for Systems Biology

Wood DK, Soriano AO, Mahadevan L,

Lawrence MS, et al, Lander ES, Getz G.