APPENDIX: COLOR FIGURES ___________________________________________________________________

Hellström-Lindberg and Cazzola (pp 52–59) Figure 1. Peripheral blood and bone marrow smears from a patient with
refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T). Left panel: peripheral blood smear showing
abundant platelets. Middle panel: Perls staining of bone marrow smear showing numerous ringed sideroblasts. Right panel: May
Grünwald-Giemsa staining of bone marrow smear showing abnormal megakaryocytes. Courtesy of Rosangela Invernizzi.

Rambaldi et al (pp 83–91) Figure 1. The histone deacetylase (HDAC) inhibitor ITF2357 can inhibit the removal of acetyl
groups and the process that leads to chromatin condensation and transcriptional repression. As a consequence, ITF2357
blocks the clonogenic activity of peripheral blood progenitor cells isolated from patients bearing the JAK2V617F mutation (Panel A).
Moreover, exposure to ITF2357 (250 nM) is followed by rapid degradation of either total and phosphorylated JAK2 protein in
JAK2V617F-mutated HEL cells (Panel B). Finally, at the same concentration, ITF2357 increases the proportion of apoptotic cells and
reduces cells in M phase (Panel C).

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 Bessler and Hiken (pp 104–110) Figure 1. The
pathophysiology of disease in patients with paroxysmal
nocturnal hemoglobinuria (PNH). Bone marrow failure and
the occurrence of PNH blood cells are the two major
components in the pathophysiology of PNH and explain the
major clinical symptoms of patients with this disease, which are
pancytopenia, hemolysis and thrombosis (see also text). The
demonstration of blood cells deficient in GPI-linked proteins is
sufficient for the diagnosis of the disease. Immune suppressive
treatment improves bone marrow failure but does not influence
the existence of PNH cells, whereas inhibition of intravascular
hemolysis improves hemolysis-associated symptoms, but has
no effect on bone marrow failure or on extravascular hemolysis.
The increased understanding of the pathophysiology has
greatly improved diagnosis and treatment of patients with this
disease. However, a few critical “?” remain that need to be
solved in order to fully cure the disease.

Bessler and Hiken (pp 104–110) Figure 2. GPI-anchored surface proteins on human
hematopoietic cells. Blood group antigens are shown in brackets “{}.” Expression only upon
activation or only in a subset of the cells is displayed in parentheses “().”
Abbreviations: PrPc, prion protein; AChE, acetylcholinesterase; LAP, leukocyte alkaline
phosphatase; EDN, eosinophil-derived neurotoxin; ADP-RT, mono ADP-ribosyl transferase
1
both in a GPI-linked and a transmembrane form
2
transmembrane-anchored isoform.

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Bessler and Hiken (pp 104–110) Figure 3. Diagnosis of paroxysmal nocturnal hemoglobinuria (PNH). (A) Ham test, the
traditional clinical assay for diagnosis of PNH, is based on the increased susceptibility of PNH red blood cells to complement-
mediated lysis. PNH (tubes 1, 2) and control (tubes 3, 4) red blood cells are incubated with serum (S), or serum in which
complement has been heat inactivated (HS). Cells and debris are pelleted, and the degree of lysis is assessed by the presence of
red pigment from hemoglobin in the serum. Only PNH red blood cells show complement-dependent lysis (tube 1), due to their lack of
expression of GPI-linked complement inhibitors CD55 and CD59, while control red blood cells are protected (tube 3). (B)
Granulocytes from a PNH patient were stained with fluorescently labeled antibody against the GPI-linked protein CD16. Strongly
positive (normal) and completely negative (PNH) cells are present. Typically, populations of both normal and PNH hematopoietic cells
reside simultaneously in the peripheral blood. (C) Diagnosis of PNH by using flow cytometry. All hematopoietic lineages can be
affected by PNH. Currently, clinical assays often assess PNH based on staining of white blood cells with fluorescently labeled
antibodies against at least two GPI-linked proteins or, as shown here using FLAER, a fluorescently labeled derivative of the bacterial
protein aerolysin, which naturally binds the GPI anchor. On the left the dot plot analysis of total peripheral blood white blood cells
(WBC) from PNH (top) and control (bottom) individuals are shown. Note that in the sample from the PNH patient a proportion of cells
have a decreased binding of FLAER (PNH cells). To the right the histograms of specific white blood cell lineages seen in the
associated dot plots show substantially reduced FLAER binding to PNH (top) on 95% of neutrophils (PMN) and monocytes (Mono),
15% of lymphocytes (Lymph), as compared to control (bottom). (D) FACS analysis of red blood cells using fluorescently labeled anti-
CD59 is used to assess the PNH red cell population and the degree of GPI-anchor deficiency. Normal individuals show uniformly
strong staining of red blood cells with CD59 ((i), hatched line shows isotype-matched control antibody). A classic PNH patient (ii)
shows distinct populations of type III cells, which are completely deficient in surface expression of GPI-linked proteins, and type I
cells, which show normal expression of GPI-linked proteins. Type II cells show a partial deficiency of GPI-linked protein surface
expression and can be seen in PNH patients either alone (iii) or in combination with type III and/or type I populations (iv).

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Bessler and Hiken (pp 104–110) Figure 4. Synthesis of the GPI-precursors proceeds in a stepwise manner. Over 29 proteins
have been shown to be involved in the biosynthetic pathway of GPI-anchor biosynthesis.15 It starts on the cytoplasmic side of the
endoplasmic reticulum (ER). The addition of the GPI-anchor precursor to the carboxy-terminus of the protein from which a block of
17-31 amino acids has been cleaved occurs on the luminal side of the ER. Insert shows the structure of mammalian GPI-anchored
proteins. GPI-anchors have a conserved structure (NH2-CH2-CH2-PO4-6Manα1-2Manα1-6Manα1-4GlcNα1-6myo-inositol-PO4-lipid),
which can be modified by the addition of an acyl chain to the inositol (not shown) and phosphoethanolamine to the first and possibly
second mannose.

Bessler and Hiken (pp 104–110) Figure 5. Schematic representation of the structure and mutations in the PIGA gene.
Coding region is shown in boxes, introns in form of dashes (not in scale), nucleotide numbers are shown above the exons. Null
mutations (frame-shift, nonsense and splicing) are indicated above. Missense mutations and in-frame mutations are shown below. All
mutations are somatic mutations with the exception of polymorphism shown in green.
Reproduced with permission from Luzzatto L and Nafa K. Genetics of PNH. In: Young NS, Moss J, eds. PNH and the GPI-linked
Proteins. San Diego: Academic Press; 2000:21-47.

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 Bessler and Hiken (pp 104–110) Figure 6. Schematic
representation of the complement cascade in normal
individuals, in patients with paroxysmal nocturnal
hemoglobinuria (PNH), and in patients with PNH
receiving the C5 inhibiting antibody eculizumab
(modified from Bessler 2005).49 In humans the
complement system consists of more than 30 plasma and
cell-surface proteins and may be activated by three
different pathways: the classical, lectin, and alternative
pathway. The classical pathway is activated by antibody–
antigen complexes, the lectin pathway involves
carbohydrate recognition by pattern-recognition receptors,
such as mannose-binding lectin (MBL) and the subsequent
activation of MBL-associated serine proteases. The
alternative pathway does not involve specific recognition
molecules. It is initiated by the covalent binding of a small
amount of C3 to hydroxyl or amine groups on the cell-
surface molecules of microorganisms. This pathway also
functions to amplify the activation of C3. The primary goal of
the activation pathway is C3b deposition on the target cell.
The activation pathway is followed by the formation of the
membrane attack complex (MAC) in the lytic pathway of
complement activation, which is necessary for the lysis of
the target: C3b, once deposited on the target cells,
becomes part of a C5 convertase. After C5b is formed by
the C5 convertase, no further proteolytic reaction occurs in
the complement cascade. The assembly of the MAC is
formed by protein-protein interaction. The deficiency of the
surface proteins CD55 and CD59 leads to the uncontrolled
lysis of PNH red cells by complement. The C5 binding
antibody blocks the lytic pathway of complement activation.
Reproduced with permission from Bessler M. Inside blood.
Blood. 2005:106:2224.49

Tichelli et al (pp 125–133) Figure 2. Pulmonary function

tests and histology of a patient with bronchiolitis
obliterans after hematopoietic stem cell transplantation
(HSCT). Flow-volume loop of a forced vital capacity maneuver.
Positive values represent expiration, negative values represent
inspiration. The trace moves clockwise for expiration followed by
inspiration. A: normal pulmonary function at one year after
HSCT. B: abnormal pulmonary function one year later, with
expiration prolongation, decreased forced expiratory volume at
one second (FEV1, 44% of the predicted value). C: histology of
bronchiolitis obliterans showing dense concentric peribronchial
fibrosis with luminal obliteration, but a relative paucity of
inflammatory cells. Note the relative sparing of the alveolar
spaces (with the courtesy of Prof. Stephan Dirnhofer, University
Hospital, Basel, Switzerland)

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 Tichelli et al (pp 125–133) Figure 4. Renal histology
showing cyclosporine toxicity. Vacuolation of the proximal
tubular epithelium (*), beaded medial hyalinosis in afferent
arteriolae (^), three glomerula with global sclerosis and one
glomerulum with compensatory hypertrophy (with the courtesy
of Prof. Stephan Dirnhofer, University Hospital, Basel,
Switzerland).

Adamson (pp 159–165) Figure 2. Hemoglobin

concentrations in relation to serum immunoreactive
erythropoietin concentrations in 74 nonhypoxemic anemic
patients with cancer (black squares) and 24 patients with
iron deficiency anemia (red squares).
Reproduced with permission from Miller CB, Jones RJ,
Piantodosi S et al. N Engl J Med.2

Adamsom (pp 159–165) Figure 3. Time course of mean

hemoglobin (Hb) in patients receiving ESA only (solid
lines) and patients receiving ESA plus IV iron (interrupted
lines). A: intention-to-treat population (n = 149); B: per protocol
population (n = 103).
Reprinted with permission from Pedrazolli et al. J Clin Oncol.
2008;26:1619-1625.

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 Deininger (pp 419–428) Figure 1. Milestones of
therapeutic response in newly diagnosed chronic phase
chronic myeloid leukemia (CML) patients treated with
standard dose imatinib.
Red shading: failure; orange shading: suboptimal response;
green shading: optimal response.
Abbreviations: CCyR,complete cytogenic response; CHR,
complete hematologic response; CMR, complete molecular
response; MMR, major molecular response; NR, no response;
Ph, Philadelphia chromosome; PHR, partial hematologic
response.

Deininger (pp 419-428 ) Figure 2. Sensitivity of Bcr-Abl kinase domain mutants to Abl kinase inhibitors.
Imatinib: sensitive (≤≤ 1000 nM), intermediate (≤≤ 3000 nM), insensitive (> 3000 nM).
≤ 50 nM), intermediate (≤
Nilotinib: sensitive (≤ ≤ 500 nM), insensitive (> 500 nM).
Dasatinib: sensitive (≤ ≤ 3 nM), intermediate (≤
≤ 60 nM), insensitive (> 60 nM).
* The IC50 value is the concentraion of inhibitor resulting in a 50% reduction in cell viability. For experimental details, see references
8,12,21,29
.
† IC50 values from Burgess et al, PNAS 2005.21
‡ IC50 values from Shah et al, Cancer Cell 2002.29
§ IC50 values estimated from Shah et al, Science 2004.8

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 Morris (pp 177–185) Figure 1. Mechanisms of
vasculopathy. Hemolysis, arginine dysregulation,
oxidative stress and uncoupled nitric oxide synthase
(NOS) are key mechanisms that contribute to the
complex vascular pathophysiology of sickle cell disease
(SCD). These events limit nitric oxide (NO) bioavailability
through several paths that ultimately provoke increased
consumption and decreased production of the potent
vasodilator, NO. Although often discussed independently,
there is significant overlap closely linking these pathways
of endothelial dysfunction that prohibit determining cause
and effect. The contribution of inflammation coupled with
antioxidant, glutathione and Apolipoprotein A-1 (Apo A)
depletion, ischemia-reperfusion injury, and acute as well
as chronic end-organ damage obscure mechanistic
boundaries further. During hemolysis, cell free hemoglobin
and arginase are simultaneously released from the
erythrocyte and profoundly contribute to low NO
bioavailability. Lactate dehydrogenase (LDH) is also
released from the erythrocyte and represents a
convenient biomarker of hemolysis that delineates the
subphenotypes of SCD.

Morris (pp 177–185) Figure 2. Consequences of low

nitric oxide (NO) bioavailability. The consequences of
decreased NO bioavailability include endothelial cell
activation, upregulation of the potent vasoconstrictor
endothelin-1, vasoconstriction, platelet activation,
increased tissue factor and activation of coagulation
pathways, all of which ultimately translates into the clinical
manifestations of sickle cell disease. NO bioavailability is
particularly vulnerable to the effects of hemolysis, an
event in sickle cell disease that contributes to the
development of the hemolytic subphenotypes, which
include pulmonary hypertension, priapism, cutaneous leg
ulceration, stroke and possibly asthma.

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Morris (pp 177–185) Figure 3. Altered arginine metabolism in hemolysis. Dietary glutamine and glutamate
serve as a precursor for the de novo production of arginine through the citrulline-arginine pathway. Arginine is
synthesized endogenously from citrulline primarily via the intestinal-renal axis. Arginase and nitric oxide synthase
(NOS) compete for arginine, their common substrate. In stem cell disease (SCD) and thalassemia, bioavailability of
arginine and nitric oxide (NO) are decreased by several mechanisms linked to hemolysis. The release of
erythrocyte arginase during hemolysis increases plasma arginase levels and shifts arginine metabolism towards
ornithine production, limiting the amount of substrate available for NO production. The bioavailability of arginine is
further diminished by increased ornithine levels because ornithine and arginine compete for the same transporter
system for cellular uptake. Despite an increase in NOS, NO bioavailability is low due to low substrate availability, NO
scavenging by cell-free hemoglobin released during hemolysis, and through reactions with free radicals such as
superoxide and other reactive NO species. Superoxide is elevated in SCD due to low superoxide dismutase activity,
high xanthine oxidase activity and potentially as a result of uncoupled NOS in an environment of low arginine and/or
tetrahydrobiopterin concentration or insufficient NADPH. Superoxide will react with NO to form reactive NO species
(RNOS) including peroxynitrite, which can contribute further to cell damage and cell death. Endothelial dysfunction
resulting from NO depletion and increased levels of the downstream products of ornithine metabolism (polyamines
and proline) likely contribute to the pathogenesis of lung injury, pulmonary hypertension and asthma in SCD. This
model has implications for all hemolytic processes. This new disease paradigm is now recognized as an important
mechanism in the pathophysiology of SCD and thalassemia.

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Kato (pp 186–192) Figure 1. Vascular based therapeutic targets in sickle cell disease (SCD). Several mechanisms have been
proposed to contribute to pathological blood flow in SCD: intravascular hemolysis, which releases arginase and hemoglobin (Hb),
which respectively reduce levels of the nitric oxide synthase (NOS) substrate arginine and consumes NO; oxygen radicals
produced by xanthine oxidoreductase (XO) and NADPH oxidase; sickle hemoglobin polymer formation, inducing stiff, noncompliant
red cells; and adhesion of sickle erythrocytes, leukocytes, and platelets to post-capillary venular endothelium. Strategies being
tested in clinical trials directed at these pathways are indicated in the boxes and described in detail in the text.

Townes (pp 193–196) Figure 2. Correction of a βS gene in

skin fibroblasts from a sickle cell patient.

Townes (pp 193–196) Figure 1. Schematic of gene

replacement protocol in iPS cells.

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Stasi Figure 1 (pp 206–211). Potential mechanisms of Helicobacter pylori–induced thrombocytopenia. A) H pylori could
induce antibody production in response to antigens, such as CagA, that crossreact against various platelet glycoprotein antigens. B)
Platelets may be activated by binding of first-generation H pylori antibodies to platelet FcγRIIA or through an interaction between H
pylori–bound von Willebrand factor (VWF) and platelet glycoprotein IB (gpIB). Activation may promote platelet clearance and antigen
presentation, which augments production of antibacterial antibodies. C) In the presence of antiplatelet antibodies, the LPS of Gram-
negative bacteria can significantly enhance Fc-dependent platelet phagocytosis. D) Epitope spreading and somatic mutation may
lead to the development of second- and third-generation antibodies that either recognize bacterially derived factors or crossreact
with platelet antigens. The production of these antibodies is no longer dependent upon the stimulation of bacterial antigens, thereby
leading to the development of chronic thrombocytopenia refractory to eradication of H pylori infection.
Abbreviations: APC, antigen-presenting cell; P, platelet.

Cazzola et al (pp 166–175) Figure 1. Reticuloendothelial

iron metabolism and recycling. Reticuloendothelial cells
(macrophages in the bone marrow and spleen, Kupffer cells in
the liver) receive their iron from the phagocytosis of nonviable
or senescent red blood cells. Heme is catabolized by heme
oxygenase 1, and the processed iron is either rapidly recycled
to the plasma through the iron exporter ferroportin, or is stored
in cytoplasmic ferritin or hemosiderin. This latter is an
aggregated and partially denatured form of cytoplasmic ferritin
enclosed in membrane-encapsulated lysosomes
(siderosomes). Plasma ferritin is a small fraction of cytoplasmic
ferritin, glycosylated and secreted through the Golgi apparatus:
its concentration reflects the amount of ferritin (and iron) in the
macrophage. Ferroportin is the iron exporter from the cell to
plasma transferrin: hepcidin, a small peptide produced in the
liver, regulates cellular iron efflux by binding to and inducing the
degradation via internalization of ferroportin.
In anemic patients receiving regular blood
transfusions, iron is primarily taken up by the reticuloendothelial
cells and then exported by ferroportin to plasma transferrin, and
thereby redistributed to parenchymal cells. This redistribution is
modulated by several factors, including the degree of ineffective
erythropoiesis through its suppressive effect on hepcidin
production.

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de Leval and Gaulard (pp 272–279) Figure 1. Overview of T-cell and NK-cell differentiation and the putative histogenetic
derivation of the major subtypes of mature T- and NK-cell neoplasms.
Mature T cells derived from precursor lymphoblasts in the thymus are genetically characterized by functional rearrangement of the
T-cell receptor (TCR) genes. Based on the structure of the TCR, two classes of T cells are recognized: αβ and γδ; both express
CD3. γδ T cells are CD4–CD8– or less often CD4–CD8+, they comprise < 5% of T cells in the peripheral blood and show a restricted
distribution mainly to the epithelia where they are involved in mucosal immunity, and to the red pulp of the spleen. αβ T cells are
divided into CD4+ (mainly helper, with Th1 or Th2 profile of cytokine-secretion) and CD8+ (mainly cytotoxic) subsets. Mature naive T
cells are found in the thymic medulla, in the circulation and in the paracortex of lymph nodes. Antigen-dependent reaction occurs in
the paracortex of lymph nodes. From the immunoblastic reaction come antigen-specific T cells of either CD4 or CD8 type, as well as
memory cells, that may recirculate and home to peripheral tissues.
NK cells derived from a bone marrow precursor are distinguished by the absence of TCR rearrangement and membrane
TCR expression. NK cells share some markers with T cells as they can express CD2, CD7, CD43, CD45RO, and cytoplasmic (but
not surface) CD3. NK cells are usually CD4–CD8– but may be CD8+, and they express one or several of the “NK-associated”
antigens (CD11b, CD16, CD56, CD57, NK receptors), none of which, except perhaps CD16, is specific since they can also be
expressed by some T cells. Both NK cells and activated cytotoxic T cells express cytotoxic proteins, T-cell intracellular antigen (TIA)-
1, perforin, and granzymeB.
Functionally, the majority of T cells are part of the specific/adaptive immune system and recognize the antigen in a MHC-
restricted fashion in the presence of an antigen-presenting cell, whereas NK cells, a subset of the γδ T cells and a minor subset of
αβ T cells are part of the innate immunity, i.e., the recognition of antigens occurs through surface receptors independently of a MHC-
restricted presentation, involving NK receptors and toll-like receptors.
Mature T/NK-cell lymphomas manifest the immunophenotypic and genetic features of post-thymic T lymphocytes or
mature NK cells. T-PLL is thought to derive from naive T cells at a stage intermediate between thymic lymphoblasts and mature naive
T cells. NK cells are the cell of origin for aggressive or chronic NK cell leukemias, and give rise to NK-cell lymphomas in tissues,
usually in the nasal area. The majority of extranodal T-cell lymphomas derive from cytotoxic T cells; one exception is mycosis
fungoides derived from effector CD4+ cells with cutaneous homing properties. γδ T cells give rise to most cases of hepatosplenic T-
cell lymphomas as well as a subset of cutaneous T-cell lymphomas. Enteropathy-associated T-cell lymphoma derives from
intraepithelial—usually αβ—T cells of the intestine. Adult T-cell lymphoma/leukemia associated with HTLV1 infection is a neoplasm
derived from a peculiar subset of CD4+ T cells with a frequent regulatory phenotype (CD25+ FoxP3+). The cellular derivation of nodal-
based T-cell lymphomas will be discussed later in the text.
Abbreviations: AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; LGL, large granular
lymphocytic; HTLV, human T-cell leukemia virus; PLL, prolymphocytic leukemia; PTCL, NOS: peripheral T-cell lymphoma, not
otherwise specified; TCL, T-cell lymphoma.

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de Leval and Gaulard (pp 272–279) Figure 2. Gene expression profiling demonstrates a molecular link between
(angioimmunoblastic T-cell lymphoma) AITL and follicular helper T (TFH) cells (adapted from de Leval et al6).
In this molecular profiling study of 18 AITL and 16 peripheral T-cell lymphomas, not otherwise specified (PTCL, NOS) samples, gene
set enrichment analyses (GSEA) were performed by using sets of genes representative of distinct normal T-cell subsets, in order to
compare the molecular signature of the tumor samples. Panels A and B show enrichment score (ES) curves generated by such
analyses. In panel A, genes discriminant between AITL and PTCL, NOS were ranked (according to the signal to noise ratio) from left
to right, and GSEA was performed by using a set of 100 genes overexpressed in normal TFH cells; the ES curve is significant,
meaning that the AITL samples display significant enrichment in the TFH signature, as compared to PTCL, NOS. In panel B, two
AITL samples consisting of purified tumor cell suspensions were compared with 16 AITL tissue samples, and GSEA showed a
significant enrichment of the tumor cell suspensions in the set of the 42 core genes (accounting for the enrichment in panel A).
Finally the finding that the imprint of the TFH signature was stronger in purified AITL tumor cells samples compared with AITL
tissues, validates that the molecular link with TFH cells was related to the neoplastic cells. Panel C show the associated heatmap of
these 42 core genes. Expression data from normal T-cell subsets, 2 AITL tumor cell suspension samples (arrows), 16 AITL tissue
samples and 16 PTCL, NOS samples are represented. Standardized expression ranges from -2.0 (blue) to 2.0 (red).

de Leval and Gaulard (pp 272–279) Figure 3. The

overlapping spectrum of nodal peripheral T-cell
lymphomas (PTCL) entities.
Nodal PTCLs comprise four main entities:
angioimmunoblastic T-cell lymphoma (AITL), ALK+
anaplastic large cell lymphoma (ALCL), ALK– ALCL
and PTCL, not otherwise specified (PTCL, NOS).
The only well-demarcated entity is ALK+ ALCL. TFH
cells have recently been identified as the cell of origin
of AITL, whereas the cellular origin of the other
entities is not known precisely. There is a lack of
specific definition criteria for PTCL, NOS, and thus
substantial overlap with AITL, and ALK– ALCL. Gene
expression profiling analyses have identified traces
of the TFH signature in a subset of PTCL, NOS,
suggesting that the spectrum of AITL may be wider
than anticipated. A small group of “follicular” PTCLs,
different from AITL, might also derive from TFH cells
and could be associated with a distinct translocation
t(5 ;9) involving ITK and SYK. The overlap between
PTCL, NOS and ALK– ALCL is accounted by a
subset of PTCLs composed of large CD30+ cells.

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Perkins and Friedberg (pp 341–348) Figure 2. A. Low-power H&E-stained section of a lymph node involved with Burkitt
lymphoma (BL) from an 82-year-old man. Note the uniform appearance of the cells, the diffuse pattern of growth, and the nuclear
debris from apoptotic cells, mostly contained within the cytoplasm of pale-staining tingible-body macrophages. B. Cytology of bone
marrow cells, as seen on Wright-Giemsa–stained aspirates and touch preps. Note the high nuclear-to-cytoplasmic ratio, moderately
abundant dark blue cytoplasm with occasional vacuoles, and nucleus with finely granular chromatin and multiple nucleoli. C.
Identification of MYC translocation by FISH analysis using “MYC break-apart probes. When together, as in a normal chromosome,
the two probes are located in close proximity and give a composite yellow color, while the probes are distinct when translocation
occurs (Taken with permission from Hecht and Aster39). D. Composite figure from paper by Hummel et al,6 depicting the results of
gene array studies, karyotype and FISH analyses. Top, bar graph depicting the karyotypic complexity of each case. The mBL Index
section depicts a heat map of the 58 mBL signature genes; blue is low expression, while yellow is high expression. IG-myc
translocations are in bright green; non-IG-myc fusions are in dark green, and myc-absent are in red. At bottom, histologic diagnosis:
bright green, BL; dark green, atypical BL; red, diffuse large B-cell lymphoma (DLBCL); grey, unclassifiable mature aggressive B-cell
lymphoma.

Appelbaum (pp 412–417) Figure 3. Potential haplotype organization of 6 of 6 matched unrelated donors.14

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 Kahl and Yang (pp 359–364) Figure 1. Histologic examples
of nodal marginal zone lymphoma (NMZL), splenic
marginal zone lymphoma (SMZL), and gastric extranodal
marginal zone lymphoma (gastric MALT lymphoma).
A. Whole mount of a lymph node with NMZL. A thickened
capsule (lower left) and interfollicular infiltrate of small B
lymphocytes and monocytoid B cells is shown. A reactive follicle
(white arrow) is surrounded by an expanded marginal zone of
monocytoid B cells while other follicles have been partially
replaced by small B cells (black arrows and inset). B. Section of
a spleen with SMZL showing marked expansion of the white
pulp by monocytoid B cells (inset). Note the lack of follicular
mantles and infiltration of monocytoid B cells into the splenic red
pulp. C. Full thickness section of gastric MALT lymphoma
showing an ulcerated epithelial surface and diffuse infiltrate of
marginal zone cells in the lamina propria that have colonized the
germinal centers of the B-cell follicles. Scattered lymphoepithelial
lesions were also present (inset).

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Kahl and Yang (pp 359–364) Figure 2. Activation of NF-κ κB and chromosomal translocations found in MALT lymphoma.
Epitopes from Helicobacter pylori can lead to activation of NF-κB through the B-cell receptor (BCR) via receptor-associated tyrosine
kinases of the SRC and SYK family, which signal a protein kinase C (PKC) family member to oligomerize BCL-10, CARMA1, and
MALT1 leading to activation of the inhibitor of NF-κB kinase (IKK) complex. The IKK complex phosphorylates the inhibitor of NF-κB
(IκB) prompting its degradation by the proteasome and allowing the NF-κB family members to translocate to the nucleus and control
NF-κB–dependent gene expression. The t(1;14) and t(14;18) translocations lead to overexpression of the BCL10 and MALT1 genes
respectively and the t(11;18) translocation produces a chimeric API2-MALT1 protein that can directly activate the IKK complex.
Constitutive activation of the NF-κB pathway by these translocations bypasses the requirement for BCR signaling and may account
for the antigen independence of cells harboring these translocations.

Haferlach (pp 400–411) Figure 1. Frequency of molecular markers and their cooperation in patients with acute myeloid
leukemia (AML) and normal karyotype (n = 1447).56

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