HAM-WASSERMAN LECTURE

Angiogenesis: A Target in Solid Tumors, Also in Leukemia?

Thomas Schmidt1 and Peter Carmeliet2,3
1Department

of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany;

of Angiogenesis and Neurovascular Link, Vesalius Research Center (VRC), VIB, Leuven,
Belgium; and 3Laboratory of Angiogenesis and Neurovascular Link, VRC, K.U.Leuven, Leuven, Belgium
2Laboratory

Targeting angiogenesis has become an established therapeutic approach to fighting solid tumor growth in cancer
patients. Even though increased angiogenesis has long been recognized in various types of hematologic malignancies,
the molecular basis underlying this angiogenic switch in leukemias remains poorly understood. The BM stroma is
gaining increasing attention for its role in promoting leukemia growth and resistance against current treatments with
tyrosine kinase inhibitors. This article provides a brief overview of the role of angiogenesis in leukemias, discusses
recent insights into the role of placenta growth factor (PlGF), a VEGF family member, as a novel disease candidate in
chronic myeloid leukemia (CML), and highlights the therapeutic potential of PlGF blockade for imatinib-resistant CML.

Introduction
Small organisms, such as the fruit fly Drosophila melanogaster or
the worm Caenorhabditis elegans, lack a proper vascular system
because oxygen can diffuse from the environment to all parts of
their bodies. In contrast, higher organisms need a system to
transport oxygen and nutrients because these substances cannot be
distributed by simple diffusion. Therefore, the establishment of a
vascular system was essential evolutionarily in organisms in which
the limits of oxygen diffusion were outgrown. Functional blood
vessels provide the basis of tissue homeostasis and growth with
the supply of oxygen and nutrients and the elimination of
metabolic degradation products. During development, endothelial progenitor cells form a primitive vascular network of small
capillaries in a process termed vasculogenesis. In subsequent
steps, this primitive network expands by a process termed
angiogenesis, in which endothelial cells (ECs) sprout and form
a more complex and elaborated vascular system. Finally, in a
process termed arteriogenesis, the coverage of EC channels
with pericytes and smooth muscle cells provides vessel maturation and stabilization.
In addition to wound healing, the cycling ovary, and the placenta
during pregnancy, most blood vessels are kept in a quiescent state
under physiological conditions in adulthood by a balanced microenvironment of pro- and anti-angiogenic factors.1 However, in pathological conditions, numerous disorders are caused or characterized
by excessive or insufficient angiogenesis. The best known of these
conditions are diseases with abnormal excessive angiogenesis such
as cancer, arthritis, chronic inflammation, infectious or autoimmune
diseases, psoriasis, choroidal neovascularization, and others.1 Conversely, several diseases are characterized by insufficient angiogenesis or vessel regression, such as preeclampsia, Alzheimer disease,
stroke, amyotrophic lateral sclerosis, diabetic neuropathy, peripheral artery disease, osteoporosis, and ischemic heart disease. Additional diseases are being categorized as angiogenic disorders.1 The
basic mechanisms of vascular branching and tumor angiogenesis
have been extensively reviewed in earlier publications.1,2 The first
part of this review focuses mainly on the key target, VEGF and its
receptors, because they are currently the targets of the US Food and
Drug Administration (FDA)approved anti-angiogenic drugs.

Hematology 2011

The process of angiogenesis is initiated in conditions under which

cells experience low oxygen tension and mount a hypoxia inducible
factor 1 (HIF-1)mediated response.3 HIF-1 is a transcription
factor that is stabilized in hypoxic conditions and activates several
genes, including the prototypic angiogenic VEGF-A (from here on
termed VEGF). VEGF is the founding member of the structurally
related VEGF family of growth factors comprising VEGF, VEGF-B,
VEGF-C, VEGF-D, and the viral homolog VEGF-E, as well as
placenta growth factor (PlGF) (Figure 1).4 These growth factors can
bind and signal through the tyrosine kinase (TK) receptors VEGFR-1,
VEGFR-2, and VEGFR-3, each with different affinities and selectivities. VEGF binds to VEGFR-1 and VEGFR-2, PlGF and
VEGF-B bind to VEGFR-1, and VEGF-C and VEGF-D bind to
VEGFR-3 and depending on the species and with a lower
affinityto VEGFR-2.5 VEGF is the most prominent of these
factors because it has a crucial role in angiogenesis and vessel
maintenance. Indeed, VEGF expression levels need to be tightly
regulated because VEGF haplodeficiency leads to embryonic lethality.6 VEGF induces a pro-angiogenic and permeability-enhancing
signal via VEGFR-2, which is abundantly expressed on ECs,
whereas signaling through VEGFR-1 and the regulation of angiogenesis by this receptor is more complex.
The following is a brief update on the status of anti-angiogenic
therapy in solid tumors and how angiogenesis influences hematogenous tumors. The role of PlGF in solid tumors and leukemia is also
discussed, and its therapeutical potential as a novel anti-angiogenic
target highlighted.

Anti-angiogenic therapy in solid tumors

In solid tumors, it is well established that the angiogenic switch
from an initial avascular tumor nodule to a rapidly growing, highly
vascularized tumor is a critical step in the process of carcinogenesis.7 The concept that tumor growth and metastasis are angiogenesis dependent and that blockage of angiogenesis could be a target
in cancer therapy was postulated in 1971 by Judah Folkman.
Anti-angiogenic therapy has now become an additional pillar in the
treatment options for several cancers.
Due to its prominent role in angiogenesis, VEGF has been in the
spotlight of research efforts that resulted in the approval of 5 FDA

Another concern, raised by at least some recent preclinical findings

in particular experimental conditions, is that VEGF signaling
inhibition might inhibit the primary tumor growth, but at the same
time also evoke an adaptation in tumor cells to a more metastatic
phenotype.23 However, these findings are highly debated, and not
reproduced by other preclinical results24 or large clinical studies.25
Further research will be needed to personalize anti-angiogenic
medicine by more optimally matching the pharmacological profile
of an anti-angiogenic therapy with correctly selected patients.
Predictive biomarkers would therefore be of enormous value, but
are sorely lacking to date.

Figure 1. Scheme illustrating the VEGF family members and their

respective receptors. (Reprinted with permission from Ruiz de
Almodovar et al.5)

-approved anti-angiogenic drugs targeting the VEGF pathway. The

first generation of these drugs is the monoclonal anti-VEGF
antibody bevacizumab (Avastin), which was approved as first-line
therapy in combination with other chemotherapy in metastatic
colorectal cancer,8 metastatic breast cancer (pending approval,
under revision),9 non-small-cell lung cancer,10 metastatic renal cell
carcinoma,11,12 and as second-line therapy in glioblastoma multiforme.13 The second-generation FDA-approved broad-spectrum
small-molecule receptor TK inhibitors include sunitinib (Sutent),
sorafenib (Nexavar), pazopanib (Votrient), and vandetanib (Zactima),
which target the VEGF receptors, PDGFRs, and others. Sunitinib,
sorafenib, and pazopanib are all approved as monotherapy for
mRCC after prolongation of the progression-free survival (PFS).14-16
Sorafenib is also approved for hepatocellular carcinoma (HCC).17
Sunitinib is also approved for imatinib (Glivec)resistant gastrointestinal stroma tumors18 and for pancreatic neuroendocrine
tumors. Vandetanib is approved for late-stage medullary thyroid
cancer.19
Notwithstanding these achievements, clinical findings have been
less overwhelming than many preclinical results, and antiangiogenic therapy is currently facing several challenges, in particular the intrinsic refractoriness and acquired evasive escape against
VEGFR blockers.20 VEGF-targeted anti-angiogenic therapy prolongs the survival of patients with certain types of tumors by
months, but it fails to induce a survival benefit in others.21
Surprisingly, bevacizumab elicits better clinical results when combined with chemotherapy, in contrast to receptor TK inhibitors. An
increasing number of trials show a transient stabilization of the
disease with even tumor regression and a prolonged PFS, but no
prolongation of the more important and clinically relevant overall
survival (OS).9,22,23 Why prolongation of PFS does not always translate
to prolongation of OS in patients undergoing anti-angiogenic
therapy remains largely speculative, and several recent overviews
have discussed various types of resistance mechanisms.21,23

Currently, a new vascular-targeting therapeutic strategy is gaining

increasingly more attention. It is well known that tumor blood
vessels are highly abnormal in structure and function, characterized
by a tortuous, chaotic, and irregular branching network (Figure
2A-B).26 In the tumor vasculature, ECs are highly activated, lose
their polarity and alignment, and detach from the basement membrane, all resulting in a leaky, fenestrated network that facilitates
bleeding and increases the interstitial fluid pressure. Apart from the
ECs, the entire vessel wall, including the basement membrane and
the covering pericytes, becomes abnormal in most tumors. Tumor
ECs are typically covered with fewer and more abnormal pericytes,
and their associated basement membrane is only loosely associated
and inhomogeneous in structure. It is suspected that this abnormal
vasculature impedes the distribution of chemotherapy and oxygen.26
Traditional anti-angiogenic therapy aims to maximally inhibit
angiogenesis and to prune existing tumor vessels; however, this
strategy can also increase the risk of aggravating hypoxia and
enhancing tumor cell invasiveness.
Recent genetic and pharmacological studies have revealed that
targeting abnormal tumor vessel function by the induction of vessel
normalization can offer alternative options for anti-angiogenic
therapy (Figure 2C). Vessel normalization can be achieved by
several different approaches, including blockade of VEGF,26 genetic modulation of the oxygen sensors prolyl hydroxylase domain
containing protein 2 (PHD2),27 targeting of mechanisms that affect
the pericyte coverage and vessel maturation, and targeting myeloid
cells via blockade or genetic loss of PlGF.28-30 Vessel normalization
could provide a means to increase the responsiveness to chemotherapy, immunotherapy, or radiation, and may contribute to
restricting tumor dissemination.

Angiogenesis and anti-angiogenic therapy in

leukemia
With the BM and the lymphatic organs being the main location for
hematologic malignancies, and leukemic cells circulating in the
peripheral blood, angiogenesis was initially considered to not or
only minimally contribute to the pathogenesis of liquid tumors.
However, by now it has become apparent that the BM vasculature
plays an important role in hematopoiesis in health and disease. For
example, endothelial and mural cells (pericytes and smooth muscle
cells) provide a specialized vascular niche for hematopoietic stem
cells (HSCs).31 Different from the osteoblastic niche, which
provides a microenvironment for long-term quiescent HSCs, the
vascular niche supports proliferation and differentiation of shortterm hematopoietic progenitors.32 It is postulated that HSCs first
leave the osteoblastic niche and are then mobilized to the vascular
niche before being released into the bloodstream.
Similarly to HSCs, a small fraction of leukemic stem cells possess
stem-cell properties with long-term self-renewal, especially in

American Society of Hematology

Figure 2. Scheme illustrating a normal blood vessel (A), the abnormalities of a tumor blood vessel (B), and a partially normalized tumor
blood vessel (C). BM indicates basement membrane; phalanx ECs, quiescent ECs; IFP, interstitial fluid pressure; PC, pericytes; M1-TAM, M1polarized tumor-associated macrophages. (Reprinted with permission from Carmeliet and Jain.26)

chronic myeloid leukemia (CML).33 Both the osteoblastic and

vascular niche are of importance for the support and maintenance of
leukemic stem cells.32 BM ECs in this vascular niche are capable of
secreting several soluble cytokines such as G-CSF, GM-CSF,
VEGF, and IL-6, which promote leukemia cell proliferation and
survival.34
The BM vasculature is different from the vasculature in other organs.
Large-nutrient-supply arteries enter the bone, where they ramify
into smaller radial arterioles that first nourish the cortical bone
(Figure 3). This cortical bone capillary network then drains into
venous sinuses in the BM that extensively anastomose with each
other and merge into larger central sinuses, from which an emissary

vein leaves the bone. The microvascular capillary network consists

of thin-walled, fenestrated sinusoidal ECs (SECs), allowing access,
transport, and egression of nutrients and cells across the microvascular wall.35 These SECs have a unique VE-cadherinVEGFR2
VEGFR3Sca1 signature.35 Due to the unique expression of
adhesion molecules, SECs allow hematopoietic stem and progenitor
cells to home and traffic through the BM. This sinusoidal network
consists only of a thin basal lamina with a single layer of ECs, but
typical pericytes are missing.36; instead, they can be covered by
SDF-1 reticular cells37 and clusters of myeloid F4/80 cells.38
The abundant densely packed surrounding hematopoietic cells
and adipocytes further support this fragile network of SECs.31
Despite its extensively branched vascular network, the adult BM

Figure 3. Diagram and photograph of the BM microvasculature. (A) Scheme illustrating the BM vasculature with an arterial supply ramifying into a
capillary network and drained by a venous sinusoidal network. (Source: http://www.accesmedicine.com.) (B) Vascular casts showing the BM
microvasculature with slender arterioles supplying an anastomosing venous network. (Source: http://visualsunlimited.photoshelter.com.)

Hematology 2011

is relatively hypoxic, with oxygen tensions approximating only

20 mmHg.3
An increase in the BM vascular density, indicative of the induction
of angiogenesis, has been observed in various hematologic diseases
such as leukemia, multiple myeloma, and myelodysplastic syndromes.39 Angiogenesis is stimulated upon infiltration of the BM
with leukemia cells in various types of human hematological
malignancies, including B-cell chronic lymphocytic leukemia,40
acute lymphoid leukemia (ALL),41 acute myeloid leukemia (AML),42
CML,43 myelodysplastic syndrome,44 multiple myeloma (MM), and
others.45-47 In accordance, an increase in microvascular density has
been used as an independent prognostic parameter for OS in
CML.48,49 However, currently, the molecular basis of the angiogenic
switch in leukemia in general and CML in particular is still poorly
characterized, and other than VEGF and angiopoietin-2, only a few
other molecules have so far been implicated in this process.50-53
Some of those molecules include soluble (s)VEGFR-1, sVEGFR-2,
basic fibroblast growth factor, IL-6, IL-8, TNF-, angiogenin, tissue
factor, and HIF-1.54-56
Even though elevated VEGF levels are a marker of poor prognosis
in hematological malignancies,51 and angiogenesis is induced in the
leukemic BM,52 much less attention has been paid to evaluate
(pre)clinically the possible benefits of VEGF-targeted treatments of
leukemia. VEGF, secreted by leukemia cells, can activate VEGF
receptors on both the leukemia cells and ECs. VEGF is also able to
induce the proliferation of these cells and can chemoprotect
leukemia cells against cytotoxic agents such as etoposide and
doxorubicin.57 In CML, the disease-causing Bcr-Abl1 fusion kinase
up-regulates the expression levels of VEGF,58 whereas the Bcr-Abl1
TK inhibitor imatinib down-regulates VEGF.59
A limited number of preclinical studies have shown that VEGFR
blockade can slow down the progression of hematologic malignancies in a tumor typespecific and context-dependent manner. For
example, in a murine xenograft T-leukemia/lymphoma model,
bevacizumab combined with doxorubicin delayed tumor growth
more than doxorubicin monotherapy alone.60 Delivery of an antiVEGFR-2 antibody or VEGF-antisense approaches also slowed
down leukemia growth in models of promyelomonocytic leukemia
and subcutaneous implanted erythroleukemia.61-63 In xenotransplantation models of human AML chloromas, vascular disrupting
agents, a new class of agents directly targeting proliferating ECs,
increased leukemia cell apoptosis, leaving, however, a residual
highly vascularized viable rim of leukemia cells. When combined
with bevacizumab, this viable tumor rest was abrogated and
enhanced leukemia regression was observed.64
Initial human studies have shown that bevacizumab is ineffective as
monotherapy in patients with refractory pretreated AML,65 whereas
combination therapy with cytostatic agents provided only a slight
survival advantage in ALL.66 In further studies, therapeutic approaches targeting the VEGF pathway in AML were tested in phase
1 and 2 trials, with promising results for several agents leading to
current phase 3 trials.67 Currently, the therapeutic potential of only a
limited number of other agents with anti-angiogenic activity is
being explored.51 For example, thalidomide and lenalidomide,
agents with a complex mechanism of action that indirectly inhibit
angiogenesis by lowering VEGF secretion from BM ECs, are being
evaluated for the treatment of MM. Both agents were FDA
approved together with dexamethasone in different settings for the
treatment of MM after showing an increased response rate in this

Figure 4. Scheme illustrating the multitasking activities of PlGF.

(Reprinted with permission from Fischer et al.73)

disease.68-71 In addition, the proteosome inhibitor bortezomib,

which induces EC apoptosis and inhibits VEGF production by
HIF-1 suppression, improved OS and increased the median time to
progression compared with dexamethasone alone and was FDA
approved for MM treatment.72 The VEGF-family member PlGF as a
disease-specific cytokine and its role in angiogenesis in solid tumors
and leukemia are discussed below.

A disease-specific cytokine: role and therapeutic

potential of PlGF
PlGF is a member of the VEGF family of growth factors that was
originally identified in the placenta, where it controls trophoblast
growth and differentiation.73 PlGF-knockout mice are born without
any abnormalities, indicating that PlGF is redundant for vascular
development and physiological vessel maintenance in adult health.
However, in pathological conditions, PlGF contributes to the
pathogenesis of various malignant, inflammatory, and ischemic
disorders.73 The expression of PlGF, unlike that of VEGF, is
low/undetectable in most organs in healthy conditions, but it
becomes highly up-regulated in pathological disease conditions.73
Clinical studies show that the expressions of PlGF and of its
receptor VEGFR1 (also known as Flt1) are increased in various
solid tumors, and in certain tumors can be correlated with disease
progression and predict poor prognosis, metastasis, and recurrent
disease in humans.73
PlGF binds and signals through Flt1 in various cell types (including
ECs, smooth muscle cells, fibroblasts, myeloid progenitor cells,
macrophages, and tumor cells) to promote tumor angiogenesis,
tumor growth, and the formation of the premetastatic niche.73,74
Therefore, in tumor biology, PlGF is a multitasking cytokine
involved in many different biological processes (Figure 4). Deletion
of the TK activity of Flt1 (Flt1TK/ mice) or treatment with Flt1
and PlGF-specific inhibitors, such as a mAb against PlGF (PlGF),
impairs inflammation and pathological angiogenesis and suppresses
tumor growth and metastasis without affecting healthy vessels.28,74
Myeloid cells can confer resistance to current anti-angiogenic
therapies (such as anti-VEGF therapy) by secreting additional
pro-angiogenic factors. Interestingly, PlGF treatment inhibits the
recruitment of macrophages and BM progenitor cells, and therefore
may help to reduce the source of angiogenic factors that contribute
to the anti-angiogenic escape of tumors.28 Tumor studies in

American Society of Hematology

PlGF-knockout mice showed that PlGF deficiency delays carcinogeninduced HCC and skin papilloma formation.29 Moreover, PlGF
silencing retards HCC in a transgenic onco-mouse model, consistent
with reports that PlGF levels are correlated with poor outcome in
HCC patients.29 These genetic and pharmacological studies identify
PlGF and Flt1 as therapeutic targets for anticancer therapy. Furthermore, unlike currently used VEGFR inhibitors, PlGF is not
expected to cause side effects resulting from effects on healthy
blood vessels.
PlGF treatment is not, however, effective in all tumors. Indeed,
whereas PlGF therapy is beneficial for cancers such as HCC or
skin epithelial tumors (papillomas), PlGF blockage or deficiency
does not inhibit tumor growth in the transgenic Rip1Tag2 model of
pancreatic -cell carcinogenesis despite expression of PlGF in this
tumor.29 The resistance of this tumor model might be due in part to
the inability of PlGF loss or inhibition to block the infiltration of
neutrophils, key mediators of the angiogenic switch in this model.29
Therefore, further testing of PlGF therapies and identifying
resistance-predictive markers will be required to determine those
tumor types for which PlGF therapy is beneficial.

A new role for PlGF in CML

CML is characterized by an unregulated growth of predominantly
myeloid cells in the BM and the subsequent appearance of these
cells in the peripheral blood. It is caused by chromosomal translocation t(9;22)(q34;q11) (Philadelphia chromosome) that gives rise
to the Bcr-Abl1 fusion kinase.75,76 This leukemogenic TK promotes
the survival and proliferation of CML cells.77 Because of its key role
in the pathogenesis of CML, most therapies have been focused on
targeting Bcr-Abl1, and the Bcr-Abl1 TK inhibitor imatinib is
currently the main therapy for the treatment of CML patients.76
However, whereas imatinib can induce molecular remission in most
patients, it fails to completely eradicate the leukemic stem cell pool,
and in some cases, patients fail imatinib therapy due to poor
tolerance, loss of response, or acquired resistance due to mutations
in the Bcr-Abl1 TK domain.75 Whereas current anti-CML therapies
are largely leukemia cell-centered, emerging evidence highlights
the importance of the BM stroma for the growth, survival, and TK
inhibitor resistance of leukemia cells.32,78
In vitro studies showing that PlGF promotes the survival of
hematopoietic precursors79 and stimulates the growth of ALL and
AML cells80 provided initial evidence for a role for PlGF in
leukemia. VEGFR-1 (Flt1) is also abundantly expressed by human
CML cells.80 This suggestive link between leukemia and PlGF
triggered interest in investigating the in vivo role of PlGF and the
therapeutic potential of pharmacological PlGF inhibition in CML.81
Of a large set of angiogenic candidates, PlGF levels in the peripheral
blood and BM plasma were up-regulated the most in a CML mouse
model and in CML patients. PlGF levels in the peripheral blood and
BM were correlated with disease burden in a preclinical CML
model.81 PlGF is only negligibly produced by CML cells, both in
vitro and in vivo in mice and humans. Instead, CML cells instruct
BM stroma cells (BMSCs) to produce increasing amounts of PlGF
in a NF-B dependent manner via an interaction of VCAM-1 on
BMSCs with VLA-4 (41 integrin) on leukemia cells (Figure 5).
Furthermore, genetic deletion of PlGF prolonged the survival of
CML-bearing mice using different models.81 This genetic phenotype was phenocopied by blockade of PlGF using the aforementioned anti-PlGF mAb (PlGF), delaying the onset and slowing
down the disease rather than altering its characteristics.81

Hematology 2011

Figure 5. Scheme illustrating the bidirectional communication

between CML leukemia cells and BMSCs. This interaction produces
PlGF, resulting in the increased metabolism and growth of CML cells.

Mechanistically, PlGF stimulated matrix deposition in the BM and

BM angiogenesis and induced the accumulation of BMSCs. Furthermore, PlGF had direct effects on leukemia cells and stimulated their
proliferation, migration, and glycolytic metabolism (Figure 5).81
This PlGF-dependent stromal cellleukemia cell cross-talk favored
an expansion of both cellular populations. Therefore, by inducing
BMSCs to up-regulate PlGF production, leukemia cells create for
themselves a fertile pro-tumorigenic soil characterized by an
increased vascular supply and an altered interstitial matrix milieu. In
turn, the increased CML expansion further stimulates additional
BMSCs to produce more PlGF, thereby fueling a feed-forward
amplification loop in a self-sustaining cycle.
Last but not least, the combination treatment of PlGF plus imatinib
resulted in significantly longer survival of an imatinib-sensitive
CML mouse model compared with each monotherapy alone.81 This
can be explained by findings that PlGF, independently of Bcr-Abl1
signaling, activated various intracellular signaling cascades in CML
cells, including PLC, ERK, and HIF-1 either in the absence or
presence of imatinib. The activated hypoxia-signaling pathway
likely increased aerobic glycolytic metabolism, well known to fuel
tumor cell growth and promote TKI resistance. These findings can
also explain why PlGF treatment prolonged the survival of CML
mice when using an imatinib-resistant variant of the CML model.81
Overall, the fact that PlGF not only affects CML cells directly but
also regulates the BM stroma can explain why PlGF blockade adds
to the activity of imatinib. By activating Bcr-Abl1independent
signaling pathways, PlGF is a leukemia cell extrinsic mechanism
capable of contributing to the resistance against Bcr-Abl1 TK
inhibitors.
Overall, these preclinical studies suggest novel therapeutic opportunities for CML, specifically for imatinib-resistant patients. Although
the translational applicability of PlGF blockage for CML still
requires further testing, the current findings stimulate further
interest in the therapeutic potential of the blockage of BM angiogenesis and targeting of the leukemia-supportive BM stroma in the
future.

Conclusion
Despite formidable progress in our current understanding of (tumor)
angiogenesis with the successful translation of anti-angiogenic

therapy from the bench to the bedside in clinical practice, there

are still many outstanding challenges. Parallelisms between angiogenesis in solid tumors and in hematological diseases have been
recognized in recent years, but we are still lacking fundamental
insight into how vessels support hematological diseases and how
this can be successfully targeted in clinical settings. Nonetheless,
further study of the molecular basis of angiogenesis in hematological malignancies and elucidating how some of these molecules can
regulate the BM stroma promises to generate new fundamental
insights required for the design of improved anti-leukemia therapy.

Disclosures
Conflict-of-interest disclosure: T.S. declares no competing financial
interests. P.C. has consulted for, received research funding from,
and has equity ownership in Thrombogenics and has consulted for
and is on the board of directors or an advisory committee for Roche.
Off-label drug use: None disclosed.

14.

15.

16.

17.
18.

19.

Correspondence
P. Carmeliet, MD, PhD, Vesalius Research Center, VIB, KU
Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven,
Belgium; Phone: 32-16-34-57-72; Fax: 32-16-34-59-90; e-mail:
peter.carmeliet@vib-kuleuven.be.

20.
21.

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