Ann Hematol (2012) 91:1513–1518

DOI 10.1007/s00277-012-1475-5

REVIEW ARTICLE

Mechanisms of defective erythropoiesis and anemia

in pediatric acute lymphoblastic leukemia (ALL)
MacGregor Steele & Aru Narendran

Received: 18 February 2012 / Accepted: 11 April 2012 / Published online: 29 April 2012
# Springer-Verlag 2012

Abstract Anemia frequently accompanies the diagnosis of
acute lymphoblastic leukemia (ALL) in children and is con-
sidered to be one of the most common clinical complications
of the disease. In addition, a low hemoglobin (Hb) level is
often responsible for fatigue and other associated symptoms
that cause a decline in the quality of life of these children.
Traditionally, a number of contributing factors such as over-
crowding of the marrow, coexisting infections, and nutritional
deficits have been used to explain this phenomenon. However,
recent advances in in vivo modeling and real-time ultrastruc-
tural analytical techniques have enabled researchers to exam-
ine leukemic bone marrow (BM) microenvironment more
closely and helped to build mechanistic models of this pro-
cess. Importantly, data from these studies show that in the
majority of cases, the required stem cell populations and the
erythropoietic growth mechanisms remain intact in leukemia.
In this report, we aim to review the current state of knowledge
regarding the cellular and molecular mechanisms implicated
in the altered erythropoiesis at the time of diagnosis of
M. Steele
Division of Pediatric Hematology, Alberta Children’s Hospital,
Calgary, Alberta, Canada
A. Narendran
Division of Oncology, Alberta Children’s Hospital,
Calgary, Alberta, Canada
A. Narendran
Pediatric Oncology Experimental Therapeutics Investigators
Consortium (POETIC) Laboratory for Pre-Clinical
and Drug Discovery Studies, University of Calgary,
Calgary, Alberta, Canada
leukemia. We propose that further understanding of the mech-
anisms of anemia in leukemia may help to manage some of its
clinical consequences more effectively as well as to yield key
insight into the process of leukemogenesis itself.
Keywords Pediatric leukemia . Hematopoiesis .
Erythropoietin . Anemia
Introduction
Approximately 75 % of children who present with acute
lymphoblastic leukemia (ALL) will have significant anemia
with hemoglobin (Hb) less than 10 g/dL [1]. Currently,
anemia remains one of the most common complications of
cancer and plays a critical role in the quality of life of these
children [2]. The severity of anemia in cancer patients may
be linked to many variables including age of the child and
tumor type, extent of the disease, and nature and duration of
treatment. A number of contributors have also been pro-
posed to account for this process; these include the effects of
a chronic disease, specific nutritional deficits, chronic bleed-
ing, neoplastic infiltration of the bone marrow (BM), inter-
current infections, and autoimmune hemolytic processes [3,
4]. Whether these factors act alone or exert their effects in
combination is currently unclear. Recent studies, reviewed
below, have also shown that critical changes may occur in
the cellular and growth regulatory molecules of the BM
microenvironment that lead to reduced erythropoiesis.

A. Narendran (*) Erythropoietin response and leukemia

Division of Pediatric Oncology, Alberta Children’s Hospital,
2888 Shaganappi Trail NW,
Calgary, Alberta, Canada T3B 6A8 The hematopoietic growth factor erythropoietin (EPO) plays
e-mail: a.narendran@ucalgary.ca a central role in the proliferation, differentiation, and
1514
maturation of the erythroid lineage. EPO is synthesized and
secreted by the renal peritubular interstitial cells and acts on
the erythroid progenitors in the BM. Normally, it is pro-
duced in response to tissue hypoxia leading to an increase in
serum levels and enhanced proliferation of erythroid pre-
cursors [5]. Erythropoietin levels in healthy nonanemic
individuals, however, remain stable within a fixed range
and show no relationship to variations in Hb levels [6]. On
the other hand, there appears to exist a complex relationship
between anemia and EPO levels in cancer. For instance, an
inverse relationship between these two variables was found
in lymphoma patients but not in solid tumor patients [7].
There is a significant body of evidence in the literature that
an inverse relationship exists between serum levels of EPO
and Hb levels in children with ALL and that the feedback
regulatory pathways remain intact in these patients [7–12].
In summary, these reports have indicated that in leukemia,
patients’ EPO levels are often appropriate for observed Hb
levels, and their BM examinations demonstrate severe im-
pairment of erythropoiesis in leukemia patients, despite
elevated EPO values. Taken together, these observations
strongly indicate that the regulatory pathways of EPO ex-
pression is functional in most children with cancer, and
more complex pathophysiolgical mechanisms are involved
in the induction of anemia.
Erythropoietin is also the critical regulator of the physi-
ological processes involved in the production of new red
cells. Co-localization studies have identified EPO synthesis
to the peritubular fibroblasts found in the deep cortex and
superficial outer medulla of the kidneys [13]. Recently, the
characterization of a cell line derived from kidney tissue
indicated the association of fibroblast-like neuronal origin
cells in renal EPO production [14]. The main target for
EPO is the BM erythroid cell expressing the EPO receptor
(EPO-R). The crucial role for EPO and its receptor has been
demonstrated by knockout experiments in which homozy-
gous negative for EPO-R mice showed severe loss of defin-
itive erythropoiesis beyond the late progenitor, colony-
forming unit-erythroid (CFU-E) stage in the fetal liver,
leading to embryonic death by E13.5 [15]. However, the
fact that these mice contained erythroid precursors sug-
gested that the commitment of stem cells to erythropoietic
lineage is independent of EPO activity.
The signal transduction cascades that are activated upon
EPO binding appear complex and seem to involve Janus
kinase (JAK2) and the signal transducer and activator of
transcription 5 (Stat 5) [16, 17]. Activation of JAK2 results
in the initiation of multiple signaling processes that subse-
quently leads to erythroid proliferation and differentiation
and the inhibition of apoptosis in these cells. Activation of
Stat 5 leads to its translocation to the nucleus and results in
the activation of a number of genes that are involved in cell
growth regulation and antiapoptotic effects [18].
Ann Hematol (2012) 91:1513–1518
Hypoxia, EPO production, and the leukemic
microenvironment
In the tumor microenvironment, hypoxia arises when the
oxygen consumption greatly exceeds its delivery. Hypoxia
is also the major regulator of EPO expression through the
activation of the transcription factor hypoxia-inducible fac-
tor 1 (HIF1), which binds to the 3′ enhancer region and
initiates the expression of EPO gene [19]. Normally, the
combined activity of HIF-1α and HIF-2α facilitate multiple
physiological processes, including erythropoiesis, angiogen-
esis, and anaerobic glucose metabolism, leading to an effec-
tive adaptation to hypoxia [20]. Studies by Wellmann et al.
have shown that the oxygen-regulated component of HIF-
1α is overexpressed in clusters of leukemic cells in pediatric
ALL BM compared to normal BM [21]. In the normal BM,
hematopoiesis has been shown to occur under relatively
hypoxic conditions in marrow regions typically located
away from blood sinus [22, 23]. It appears that significant
changes in these physiological processes do occur in the
leukemic marrow. For example, there is evidence for in-
creased microvessel density in the BM of patients with
hematologic malignancies including ALL [24]. Further-
more, this proangiogenic nature of the ALL marrow
increases in relapsed ALL as shown by increased VEGF
levels, which is associated with poor prognosis and de-
creased molecular response to chemotherapy [21]. Since
hypoxia- and hypoxia-related genes such as HIF-1 are crit-
ical in hematopoiesis in general [25], an increase in angio-
genesis may contribute indirectly to altered erythropoiesis.
Recent studies by Drogat et al. have shown that VEGF
overexpression in the embryonic erythroid development
model leads to blocks in the development of both primitive
and definitive erythroid progenitors through GATA 1 mod-
ulation [26]. However, additional studies are required to
investigate a direct role, if any, of increased VEGF or the
process of angiogenesis itself on decreased erythropoiesis
seen in the leukemic BM.
A role for leukemic marrow microenvironment
in defective red cell production
The process of hematopoiesis including erythropoiesis
involves a complex and multistep interaction between the
hematopoietic stem cells and the stromal cells of the BM
microenvironment. The stromal cells provide the necessary
growth stimulatory and regulatory signals through cell–cell
interactions and soluble factors. Hence, a defect in the
production of functional erythrocytes could result from ab-
normal progenitor stem cells, abnormal stromal cells, or by
defects in the critical communication pathways between
these two cell components. Accordingly, a number of
Ann Hematol (2012) 91:1513–1518
studies have explored the role of BM microenvironment in
relation to anemia in malignancy using in vitro colony
assays and transgenic animal models. Earlier studies by
Urabe et al. have evaluated the function of BM erythroid
progenitor cells from acute leukemia patients in semisolid
culture assays [27]. It was found that during the active phase
of the disease, compared to normal marrow, leukemia
patients have lower numbers of both primitive erythroid
progenitor cells (burst-forming units-erythroid (BFU-e))
and later stage cells (CFU-e). However, when remission
was achieved, both of these components returned to within
normal range. In fact, there were no differences in peripheral
blood BFU-e between normal and leukemia patients. It is of
interest to note the differences in findings seen in studies
using cells from children who were in remission but receiv-
ing chemotherapy that showed decreased colony formation
compared to cells obtained from patients who were off
treatment where BFU-e and CFU-e are within the normal
range (see discussion in Ref. [27]). Since both appropriate
and reduced levels of EPO have been reported in leukemia
patients, Dainiak et al. examined the colony-forming re-
sponse to EPO by progenitor cells from leukemia BM
[28]. The colony-forming ability of these cells was found
to be normal at all EPO concentrations tested, suggesting, at
least in vitro, CFU-e and BFU-e EPO sensitivity to EPO is
not compromised. Additional studies have explored the
question of physical constraints placed upon erythroid pro-
genitors in the leukemic BM. For example, Prolaron et al.
have found that, compared to controls, the numbers of
circulating erythroid progenitors were significantly in-
creased in many ALL patients [29]. Also, there was an
abnormal size distribution of BFU-e derived colonies that
consisted of an increased number of small size colonies.
These data led the investigators to postulate that BM
crowding-out of the normal progenitors, most likely in ad-
dition to disturbances in normal development, could be
occurring under these conditions. However, suppression of
normal hematopoiesis can occur in a setting of relatively
low leukemic burden, which suggests that it is unlikely that
anatomic crowding-out of normal hematopoietic progenitors
is solely responsible for the reduction in hematopoiesis in
the leukemic marrow. Whether the ALL leukemic blasts
directly affect the replication and maturation of normal
hematopoietic progenitors leading to anemia was addressed
by the elegant experiments of Estrov and Freedman [30].
Contrary to the findings seen with AML blasts, irradiated
ALL cells and their conditioned media were, in fact, stimu-
latory to colony growth in vitro, suggesting that the growth
suppression of normal marrow constituents is not mediated
by simple inhibitory mechanisms derived from leukemia
cells. More recently, using in vivo imaging in a xenograft
model, Colmone et al. have investigated whether normal
and leukemic cells compete for niche resources in the BM
1515
[31]. It was found that leukemic cells disrupt normal hema-
topoietic progenitor cell BM niches and create aberrant
microenvironments, areas that sequester transplanted human
CD34+ cells. In addition, in the leukemic mice, the number
of transplanted cells declined and failed to mobilize into
circulation in response to cytokine stimulation. This sug-
gested that the tumor microenvironment causes hematopoi-
etic progenitor cell dysfunction by seizing normal
hematopoietic niches.
Normally, the survival and development of hematopoietic
stem cells are stringently regulated by their bidirectional
communication with stromal cells in specialized BM niches.
Leukemia stem cells (LSCs) have been thought to play a key
role in the initiation and possibly the growth and survival of
leukemia. It has been proposed that LSC may hijack these
communication mechanisms, thereby enabling them to ac-
quire a sanctuary site for survival and relapse [32]. Such
alterations may also potentially lead to the loss of effective
hematopoietic niches and subsequently to reduced erythro-
poiesis. This hypothesis is supported by the cell transfer
experiments of Hu et al., which have shown that in the
Notch1-induced murine T-cell leukemia model, normal
HSCs are rendered quiescent in the leukemic animal but
are functional when transplanted into normal recipients,
whereas normal HSCs transplanted into leukemic recipients
show progressive suppression of growth as leukemia devel-
ops [33]. Currently, however, the exact mechanisms and
pathways by which LSCs are able to acquire dominance
over critical BM niches remain to be elucidated. In addition,
experimental studies are also needed to determine the extent
to which such alterations in the normal hematopoietic niches
by malignant leukemic clones translate to decreased eryth-
ropoiesis and anemia in children with ALL.
Erythroid lineage commitment and gene fusion
abnormalities in leukemia
The t(12;21)(p13;q22) translocation and the resulting ETV6/
RUNX1 (TEL/AML1) fusion gene is present in approximate-
ly 25 % of childhood B-cell precursor ALL and appears to
confer a better prognosis. Gene expression studies have
shown that, compared to other subgroups of ALL, ETV6/
RUNX1-positive leukemia have a relatively higher expres-
sion of EPO-R, and it has been postulated that signaling by
EPO-R might be important in the pathogenesis of this sub-
type [34]. This notion is supported by the studies of Inthal et
al. showing that EPO-R is upregulated by stable transfection
of ETV6/RUNX into HEK 293 and Ba/F3 cells [35]. It was
also found that the median Hb levels of children with ETV6/
RUNX1-positive ALL is significantly lower compared to
other leukemias. However, the inverse correlation between
Hb and EPO levels indicated that EPO production is
1516
adequate for the Hb levels observed in these patients. Also,
the finding that EPO-R mRNA expression did not change as
a function of Hb levels suggested that EPO might not be a
critical regulator of EPO-R mRNA upregulation in this
subgroup. The overexpression of EPO-R in the ETV6/
RUNX1 leukemia also indicated the possibility that the cell
in which the gene fusion occurs initially might be a progen-
itor cell with erythroid potential [35]. However, so far,
current animal models of ETV6/RUNX1 fusion gene expres-
sion have failed to provide evidence for differentiation im-
pairment in erythroid precursor cells [35–37]. On the other
hand, acute myeloid leukemia (AML) with the t(8;21) trans-
location resulting in the expression of the AML1-ETO (AE)
fusion protein have been shown to manifest impaired ery-
throid differentiation and maturation, a process that is likely
to occur before lineage commitment or at an early stage of
erythroid differentiation [38]. Studies by Choi et al. have
shown that blockade of GATA-1 acetylation by AML1-ETO
correlates with its inhibitory effects on primary erythroid
lineage commitment [38].
EPO Release
Normal Bone Marrow
Erythropoiesis
O2 consumption
Hypoxia
Fig. 1 Schematic illustration of processes that have been proposed to
impact on erythropoiesis in the leukemic marrow. The increasing
presence of leukemia cells generates a hypoxic environment in areas
of bone marrow in ALL patients. This leads to increased angiogenesis
and the growth of malignant cells that, in turn, disrupt the marrow
microenvironment and the critical communication mechanisms be-
tween the stroma and hematopoietic stem cells. Anemia and low
Ann Hematol (2012) 91:1513–1518
Implications of anemia in pediatric ALL
A number of recent reports have evaluated various present-
ing features of ALL to treatment outcome in large clinical
trials [39, 40]. Earlier, there have been indications that
reduced Hb at presentation may correlate with better out-
come [41]. However, multivariate analyses reported in sub-
sequent studies have not predicted Hb levels as an
independent predictor [42, 43]. Variations in Hb levels seen
among different subtypes of ALL are a confounding factor
in these analyses. A report by Sandoval et al. has shown that
secondary t(9;11) AML, which has a clearly inferior surviv-
al rate compared to de novo disease, presents with higher Hb
levels [44]. Since biologically distinct subtypes confer dif-
ferent outcomes in childhood leukemia, whether there is a
correlation between the Hb levels and leukemia subtypes
has been evaluated by Teuffel et al. [45]. This study inves-
tigated a cohort of 1,162 pediatric ALL patients and the
overall association between the degree of anemia and leu-
kemia subtype as well as event-free survival (EFS) rates of
Anemia in ALL
Hypoxia
Hemoglobin
Leukemia Bone Marrow
Suitable micro- environment and precursors are
unavailable for EPO to act on
Disruption of Niche,
Loss of stromal
Zone of communications
Hypoxia
Loss of Normal
Erythropoiesis
Angiogenesis
VEGF Micro-vessel density
HIF-1a
Red cells Erythroid precursors
Leukemia cell
EPO
Stroma
Vasculature
hemoglobin that result as a consequence that ultimately leads to en-
hanced EPO production by kidneys. Normally, this increased EPO
results in increased erythropoietic activity that occurs in relatively
hypoxic areas away from blood sinus. In the leukemic marrow, how-
ever, such processes are reduced as suitable niches containing appro-
priate erythroid progenitors are unavailable for EPO to act on
Ann Hematol (2012) 91:1513–1518
these patients. It was found that leukemia subtypes with
favorable outcome appear to have lower Hb levels (<80 g/
L) at presentation, and higher Hb levels were observed in
high-risk groups such as T-ALL and Ph + ALL. Overall, it
appears that the degree of anemia may be distributed in a
nonrandom fashion among different risk-based subgroups
and that the patients in lower-risk groups tend to have lower
Hb levels. However, currently, it is unclear if these differ-
ences reflect an observation bias as patients with more
pronounced anemia do get started on treatment earlier or
the effects on erythropoiesis is also susceptible to distinct
molecular mechanisms that govern the growth, survival, and
treatment response of different leukemia subgroups.
Conclusion
Erythropoiesis is a complex biological process that requires
the cooperation between the progenitor cell populations and
stromal, hormonal, immune, nutritional, and other physio-
logic regulators of host homeostasis. In the recent past,
research has been focused on various aspects of erythropoi-
esis and how red cell production and survival have been
altered in children with leukemia. These investigations in-
volved molecular analyses of transcription factors and apo-
ptotic mechanisms that are deregulated during the leukemic
state as well as the alterations in the BM niche and stromal
cell physiology. The schematic illustration presented in
Fig. 1 summarizes some of the mechanisms that have been
thought to play a role in the altered erythropoiesis seen in
children with leukemia. What we have learned so far indi-
cates that, in most cases, essential stem cells and critical
feedback growth regulatory mechanisms remain intact at the
onset in leukemia patients. However, alterations and the
presence of an unsupportive microenvironment appear to
play a key role in this process. This has clear implications
for the evaluation of recombinant human erythropoietin
(rHuEPO) as a treatment modality in these children. How-
ever, there is also increasing evidence to suggest that the
establishment of leukemia-rich locales in the marrow may
interfere with the orientation of critical stem cell populations
and their development [31, 33]. This underscores the impor-
tance of further research into the factors and pathways that
regulate the growth and survival of normal hematopoietic
progenitor cells. Similarly, additional research is needed to
understand leukemia-induced changes of the normal mar-
row and to define the composition of malignant niches [46].
The observation that leukemia subtype itself is a determi-
nant in the manifestation of anemia emphasizes the need to
include biological correlative studies in future trials to un-
cover the clinical relevance of anemia in patients with
different leukemia subtypes. Importantly, our current knowl-
edge regarding this phenomenon must also advance in order
1517
to devise effective strategies to reduce the effects of anemia
on the quality of life of children with leukemia. These
studies could provide useful information about the patho-
physiology of both disease-related anemia as well as
therapy-related anemia, although these two processes may
not have completely overlapping mechanisms. Finally, fur-
ther studies on the mechanisms of anemia in ALL may also
offer key knowledge regarding the malignant BM microen-
vironment and the regulation of LSCs that are critically
dependent on such specialized niches. This information
may play a vital role in the identification of effective targets
for therapeutics for leukemia in the future.
Acknowledgments We thank Gaya Narendran for assistance with
the illustration provided in this review. This study was supported, in
part, by the Alberta Children’s Hospital Foundation.
References
1. Ching-Hon Pui (2006) Acute lymphoblastic leukemia. In: Ching-Hon
Pui (ed) Childhood leukemias, 2nd edn. Cambridge University Press,
pp 439–472
2. Michon J (2002) Incidence of anemia in pediatric cancer patients
in Europe: results of a large, international survey. Med Pediatr
Oncol 39(4):448–450
3. Ludwig H, Fritz E (1998) Anemia in cancer patients. Semin Oncol
25(3 Suppl 7):2–6
4. Jacober ML, Mamoni RL, Lima CS, Dos Anjos BL, Grotto HZ
(2007) Anaemia in patients with cancer: role of inflammatory
activity on iron metabolism and severity of anaemia. Med Oncol
24(3):323–329
5. Graber SE, Krantz SB (1978) Erythropoietin and the control of red
cell production. Annu Rev Med 29:51–66
6. Hellebostad M, Hågå P, Cotes PM (1988) Serum immunoreactive
erythropoietin in healthy normal children. Br J Haematol 70
(2):247–250
7. Kalmanti M, Kalmantis T (1989) Committed erythroid progenitors
and erythropoietin levels in anemic children with lymphomas and
tumors. Pediatr Hematol Oncol 6(2):85–93
8. Hellebostad M, Marstrander J, Slørdahl SH, Cotes PM, Refsum
HE (1990) Serum immunoreactive erythropoietin in children with
acute leukaemia at various stages of disease—and the effects of
treatment. Eur J Haematol 44(3):159–164
9. Dowd MD, Morgan ER, Langman CB, Murphy S (1997) Serum
erythropoietin levels in children with leukemia. Med Pediatr Oncol
28(4):259–267
10. Kim M, Lee J, Wu C, Cho S, Lee K (2002) Defective erythropoi-
esis in bone marrow is a mechanism of anemia in children with
cancer. J Kor Med Sci 17(3):337–340
11. Corazza F, Beguin Y, Bergmann P, André M, Ferster A, Devalck C,
Fondu P, Buyse M, Sariban E (1998) Anemia in children with
cancer is associated with decreased erythropoietic activity and not
with inadequate erythropoietin production. Blood 92(5):1793–
1798
12. Johannsen H, Jelkmann W, Wiedemann G, Otte M, Wagner T
(1989) Erythropoietin/haemoglobin relationship in leukaemia and
ulcerative colitis. Eur J Haematol 43(3):201–206
13. Bachmann S, Le Hir M, Eckardt KU (1993) Co-localization of
erythropoietin mRNA and ecto-5′-nucleotidase immunoreactivity
1518
in peritubular cells of rat renal cortex indicates that fibroblasts
produce erythropoietin. J Histochem Cytochem 41(3):335–341
14. Frede S, Freitag P, Geuting L, Konietzny R, Fandrey J (2011)
Oxygen-regulated expression of the erythropoietin gene in the
human renal cell line REPC. Blood 117(18):4905–4914
15. Lin CS, Lim SK, D’Agati V, Costantini F (1996) Differential
effects of an erythropoietin receptor gene disruption on primitive
and definitive erythropoiesis. Genes Dev 15;10(2): 154–64
16. Testa U (2004) Apoptotic mechanisms in the control of erythro-
poiesis. Leukemia 18(7):1176–1199
17. Wojchowski DM, Gregory RC, Miller CP, Pondit AK, Pircher TJ
(1999) Signal transduction in the erythropoietin system. Exp Cell
Res 253:143–156
18. Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF
(1999) Fetal anemia and apoptosis of red cell progenitors in
Stat5a−/−5b−/− mice: a direct role for Stat5 in Bcl-X(L) induction.
Cell 98(2):181–191
19. Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE (1991)
Hypoxia-inducible nuclear factors bind to an enhancer element
located 3′ to the human erythropoietin gene. Proc Natl Acad Sci
U S A 88(13):5680–5684
20. Semenza GL (2000) HIF-1: using two hands to flip the angiogenic
switch. Cancer Metastasis Rev 19(1–2):59–65
21. Wellmann S, Guschmann M, Griethe W, Eckert C, von Stackelberg
A, Lottaz C, Moderegger E, Einsiedel HG, Eckardt KU, Henze G,
Seeger K (2004) Activation of the HIF pathway in childhood ALL,
prognostic implications of VEGF. Leukemia 18(5):926–933
22. Scortegagna M, Morris MA, Oktay Y, Bennett M, Garcia JA
(2003) The HIF family member EPAS1/HIF-2alpha is required
for normal hematopoiesis in mice. Blood 102(5):1634–1640
23. Weiss L, Geduldig U (1991) Barrier cells: stromal regulation of
hematopoiesis and blood cell release in normal and stressed murine
bone marrow. Blood 78(4):975–990
24. Perez-Atayde AR, Sallan SE, Tedrow U, Connors S, Allred E,
Folkman J (1997) Spectrum of tumor angiogenesis in the bone
marrow of children with acute lymphoblastic leukemia. Am J
Pathol 150(3):815–821
25. Adelman DM, Maltepe E, Simon MC (2000) HIF-1 is essential for
multilineage hematopoiesis in the embryo. Adv Exp Med Biol
475:275–284
26. Drogat B, Kalucka J, Gutiérrez L, Hammad H, Goossens S, Farhang
Ghahremani M, Bartunkova S, Haigh K, Deswarte K, Nyabi O,
Naessens M, Ferrara N, Klingmüller U, Lambrecht BN, Nagy A,
Philipsen S, Haigh JJ (2010) Vegf regulates embryonic erythroid
development through Gata1 modulation. Blood 116(12):2141–2151
27. Urabe A, Murphy MJ Jr, Haghbin M, Gee TS (1979) Erythroid
progenitors (BFU-e and CFU-e) in acute leukaemia. J Clin Pathol
32(7):666–669
28. Dainiak N, Kulkarni V, Howard D, Kalmanti M, Dewey MC,
Hoffman R (1983) Mechanisms of abnormal erythropoiesis in
malignancy. Cancer 51(6):1101–1106
29. Praloran V, Klausman M, Naud MF, Harousseau JL (1989) Blood
erythroid progenitors (CFU-E and BFU-E) in acute lymphoblastic
leukemias. Blut 58(2):75–78
30. Estrov Z, Freedman MH (1991) Acute lymphoblastic leukemia
blast cells do not inhibit bone marrow hematopoietic progenitor
colony formation. Exp Hematol 19(3):221–225
31. Colmone A, Amorim M, Pontier AL, Wang S, Jablonski E, Sipkins
DA (2008) Leukemic cells create bone marrow niches that disrupt
the behavior of normal hematopoietic progenitor cells. Science 322
(5909):1861–1865
32. Lane SW, Scadden DT, Gilliland DG (2009) The leukemic stem
cell niche: current concepts and therapeutic opportunities. Blood
114(6):1150–1157
Ann Hematol (2012) 91:1513–1518
33. Hu X, Shen H, Tian C, Yu H, Zheng G, XuFeng R, Ju Z, Xu J,
Wang J, Cheng T (2009) Kinetics of normal hematopoietic stem
and progenitor cells in a Notch1-induced leukemia model. Blood
114(18):3783–3792
34. Fine BM, Stanulla M, Schrappe M, Ho M, Viehmann S, Harbott J,
Boxer LM (2004) Gene expression patterns associated with recur-
rent chromosomal translocations in acute lymphoblastic leukemia.
Blood 103:1043–1049
35. Inthal A, Krapf G, Beck D, Joas R, Kauer MO, Orel L, Fuka G,
Mann G, Panzer-Grümayer ER (2008) Role of the erythropoietin
receptor in ETV6/RUNX1-positive acute lymphoblastic leukemia.
Clin Cancer Res 14(22):7196–7204
36. Tsuzuki S, Seto M, Greaves M, Enver T (2004) Modeling first-hit
functions of the t(12;21) TEL-AML1 translocation in mice. Proc
Natl Acad Sci U S A 101:8443–8448
37. Sabaawy HE, Azuma M, Embree LJ, Tsai HJ, Starost MF, Hickstein
DD (2006) TEL-AML1 transgenic zebrafish model of precursor B
cell acute lymphoblastic leukemia. Proc Natl Acad Sci U S A
103:15166–15171
38. Choi Y, Elagib KE, Goldfarb AN (2005) AML-1-ETO-mediated
erythroid inhibition: new paradigms for differentiation blockade by
a leukemic fusion protein. Crit Rev Eukaryot Gene Expr 15:207–
216
39. Gaynon PS, Angiolillo AL, Carroll WL, Nachman JB, Trigg ME,
Sather HN, Hunger SP, Devidas M, Children’s Oncology Group
(2010) Long-term results of the children’s cancer group studies for
childhood acute lymphoblastic leukemia 1983–2002: a Children’s
Oncology Group Report. Leukemia 24(2):285–297, Epub 2009
Dec 17
40. Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick
NJ, Reaman GH, Carroll WL. Improved survival for children and
adolescents with acute lymphoblastic leukemia between 1990 and
2005: a report from the Children’s Oncology Group. J Clin Oncol.
2012 Mar 12. [Epub ahead of print]
41. Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauter S,
Henze G, Zimmermann M, Lampert F, Havers W, Niethammer D
(1994) Chemotherapy in 998 unselected childhood acute lympho-
blastic leukemia patients. Results and conclusions of the multicen-
ter trial ALL-BFM 86. Blood 84(9):3122–3133
42. Donadieu J, Auclerc MF, Baruchel A, Leblanc T, Landman-
Parker J, Perel Y, Michel G, Cornu G, Bordigoni P, Sommelet
D, Leverger G, Hill C, Schaison G (1998) Critical study of
prognostic factors in childhood acute lymphoblastic leukae-
mia: differences in outcome are poorly explained by the most
significant prognostic variables. Fralle Group. French Acute
Lymphoblastic Leukaemia study group. Br J Haematol 102
(3):729–739
43. Hann I, Vora A, Harrison G, Harrison C, Eden O, Hill F, Gibson B,
Richards S (2001) UK Medical Research Council’s Working Party
on Childhood Leukaemia. Determinants of outcome after intensi-
fied therapy of childhood lymphoblastic leukaemia: results from
Medical Research Council United Kingdom acute lymphoblastic
leukaemia XI protocol. Br J Haematol 113(1):103–114
44. Sandoval C, Head DR, Mirro J Jr, Behm FG, Ayers GD,
Raimondi SC (1992) Translocation t(9;11)(p21;q23) in pediat-
ric de novo and secondary acute myeloblastic leukemia. Leu-
kemia 6(6):513–519
45. Teuffel O, Stanulla M, Cario G, Ludwig WD, Rottgers S, Schafer
BW, Zimmermann M, Schrappe M, Niggli FK (2008) Anemia and
survival in childhood acute lymphoblastic leukemia. Haematolog-
ica 93(11):1652–1657
46. Carlesso N, Cardoso AA (2010) Stem cell regulatory niches and
their role in normal and malignant hematopoiesis. Curr Opin
Hematol 17(4):281–286