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HEMATOPOIESIS
From the Whitehead Institute for Biomedical Research
and Department of Biology, Massachusetts Institute of Technology,
Cambridge, MA; Department of Pathology, Children's Hospital;
Department of Laboratory Medicine, Children's Hospital, Harvard
Medical School; Renal Division, Beth Israel Deaconess Medical Center
and Harvard Medical School, Boston, MA.
Erythropoietin (Epo) controls red cell production in the basal
state and during stress. Epo binding to its receptor, EpoR, on
erythroid progenitors leads to rapid activation of the transcription factor Stat5. Previously, fetal anemia and increased apoptosis of fetal
liver erythroid progenitors were found in
Stat5a Formation of red blood cells is continuous
throughout life. The primary erythropoietic regulator is the cytokine
hormone erythropoietin (Epo). Binding of Epo to its receptor, EpoR,
expressed by erythroid progenitors, is essential for the formation of
red blood cells1 and for the maintenance of basal
erythropoiesis. In addition, Epo regulates the erythropoietic stress
response in conditions that lower tissue oxygen tension.2
The molecular and cellular mechanisms that allow Epo to regulate
erythropoiesis through a wide dynamic range are largely unknown.
Stat5 is a latent cytoplasmic transcription factor activated by EpoR as
well as many other hematopoietic and nonhematopoietic cytokine
receptors.3-6 Following EpoR activation, Stat5 binds to
phosphorylated tyrosines on EpoR, and itself becomes
tyrosine-phosphorylated. This results in its dimerization and
translocation to the nucleus where it initiates transcription of target
genes (reviewed by Bromberg and Darnell7). Known Stat5
targets include tissue-specific genes as well as genes regulating cell
growth.8-10 Recently, we and others11-14 have
shown that in a number of erythroid and hematopoietic cell lines Stat5
induces the immediate early expression of the antiapoptotic gene
bcl-xL, by directly binding to Stat5 consensus sites in the bcl-x gene. Consistent with this, Stat5 has an
antiapoptotic effect in erythroid cell lines,11 and
dominant-negative Stat5 molecules increased apoptosis and inhibited
growth of cultured fetal liver erythroid progenitors.11,15
Mice mutant for both Stat5 isoforms, Stat5a and Stat5b, were initially
reported to have apparently normal hematocrit and hemoglobin concentrations.16 However, we found that Stat5 is critical
during fetal erythropoiesis.11 The first wave of
erythropoiesis in the embryo generates large nucleated red cells in the
yolk sac. This is replaced by definitive erythropoiesis in fetal liver, generating smaller, adult-type enucleated red cells. At embryonic day
13.5, definitive erythropoiesis predominates and becomes essential for
survival. At this stage of development, we found that
Stat5a Two possible mechanisms might account for fetal anemia in
Stat5a To distinguish these 2 models, we assessed erythropoiesis in adult
Stat5a Mice
Hematocrit, hemoglobin, and red cell indices
Flow cytometry Spleens were mechanically dissociated by pushing with a syringe plunger through a 70-µ strainer in the presence of phosphate-buffered saline and 0.5% bovine serum albumin (PBS/0.5% BSA). Bone marrow cells were resuspended in PBS/0.5% BSA. Freshly isolated bone marrow or spleen cells were immunostained at 4°C in PBS/0.5% BSA in the presence of either mouse IgG (200 µg/mL, Pharmingen, San Diego, CA) or 5% mouse serum, to block Fc receptors. Cells were incubated with phycoerythrin (PE)-conjugated anti-Ter119 (Pharmingen, 1 µg/mL) and biotin-conjugated anti-CD71 (Pharmingen, 1 µg/mL) antibodies for 20 minutes, followed by a 15-minute incubation with allophycocyanin (APC)-conjugated streptavidin (Molecular Probes, Eugene, OR). Cells were also stained with propidium iodide to exclude dead cells from analysis. Where apoptosis was also measured immunostaining for Ter119 and CD71 was followed by a 15-minute incubation with fluorescein isothiocyanate (FITC)-conjugated annexin V and propidium iodide (Pharmingen) as per the manufacturer's protocol. To measure bcl-xL, cells were first surface immunostained for Ter119 and CD71. Cells were then fixed with 3% paraformaldehyde in PBS/2% sucrose at 4°C for 1 hour, permeabilized with 0.1% Triton X-100 for 5 minutes, and stained in PBS/1%BSA at 37°C for 30 minutes with polyclonal rabbit anti-bcl-x antiserum (1:200, Pharmingen) and Alexa Fluor 488 goat anti-rabbit IgG (Molecular Probes, A-11034, 10 µg/mL). Flow cytometry was carried out on a Becton Dickinson FACSCalibur (Franklin Lakes, NJ).Cytospins Freshly isolated hematopoietic cells (from spleen, bone marrow, or fetal liver) were labeled for Ter119 and CD71, and sorted according to regions as indicated in Figure 4. Cytospin preparations of cells from each region were stained with May-Grunwald Giemsa (Sigma Diagnostics).Phenylhydrazine stress test Mice with a baseline hematocrit of at least 35% were used. Mice were injected subcutaneously on each of days 0,1, and 3 with 40 mg/kg of phenylhydrazine hydrochloride solution in PBS. Blood (40-150 µL) was obtained from the tail vein on days 0, 3, 6, and 9 for hematocrit and reticulocyte count measurements. Reticulocyte count was measured by counting the number of reticulocytes and red cells on blood smears made after staining of freshly drawn blood with new methylene blue "N" (Ricca Chemical, Arlington TX). At least 500 cells per mouse were counted for each time point. The corrected reticulocyte count was calculated as described in the legend to Figure 2.Histopathology Freshly isolated neonatal or adult spleens were fixed in buffered neutral 10% formalin (VWR, West Chester, PA). Paraffin-embedded tissue was sectioned, mounted, and stained with hematoxylin and eosin.Mouse serum Epo was measured by a sandwich enzyme-linked immunosorbent assay (ELISA) as described.20
Developmental anemia and anemia in adults in
Stat5a  /5b/ mice are anemic by
embryonic day 13.511 (Figure
1). To assess whether anemia persists
postnatally, we looked at Stat5a/5b/
neonates within 24 hours of birth. We found that more than 95% of
Stat5a/5b/ neonates are born anemic.
The Stat5a/5b/ neonatal hematocrit is
28.9% ± 0.9% (mean ± SE, n = 65), compared with
41.3% ± 0.5% for Stat5a+/5b+/ neonates
(n = 88) and 47.6% ± 1.6% for wild-type neonates in the same
litters (n = 12, Figure 1 and Table 1).
Anemia persists until weaning, at approximately 3.5 weeks (Table 1). By
5 weeks of age, approximately 30% of
Stat5a/5b/ mice have recovered a
near-normal hematocrit, whereas the rest remain anemic. The mean
hematocrit of Stat5a/5b/ mice at 5 to
12 weeks is 27.9% ± 2.0%, compared with 45.2% ± 0.9% in the
wild-type mice (Table 1). The proportion of
Stat5a/5b/ mice with near-normal
hematocrit increases to more than 50% with older mice (Figure 1). This
may reflect decreased survival of anemic young adult mice (M.S.,
H.-S.N., H.F.L., unpublished observations, 1999-2001). In
addition to a lower hematocrit,
Stat5a/5b/ mice show a small
decrease in mean red blood cell volume (MCV) (Table 1).
Anemic Stat5a Adult Stat5a / 5b/ mice may reflect the
inability of erythroid progenitors lacking Stat5 to generate the high
erythropoietic rate required during development.11 The
near-normal hematocrit of some adult
Stat5a/5b/ mice (Figure 1) may be
explained by the relatively low rate of erythropoiesis required to
maintain the steady-state hematocrit in adult mice. Alternatively,
qualitative differences between fetal/neonatal erythropoiesis and
erythropoiesis in the adult may make Stat5 relatively redundant in
adult erythropoiesis. To distinguish these 2 possibilities, we selected
adult Stat5a/ 5b/ mice with a
near-normal hematocrit and tested their ability to generate high
erythropoietic rates in response to stress. The Stat5a/5b/ mice used in this experiment
had an initial hematocrit of at least 36% and a mean initial
hematocrit of 41%. We subjected these mice and wild-type controls to a
brief, chemically induced hemolytic anemia (Figure
2) by injecting them with phenylhydrazine
subcutaneously on days 0, 1, and 3. Their hematocrit and reticulocyte
counts were monitored over the following 9 days. Reticulocytes are
newly generated red blood cells and typically become mature red cells within 2 days. Therefore, the proportion of reticulocytes in the red
cell population allows an assessment of erythropoietic
rate.21 In the basal state, 2% or less of total red cells
were reticulocytes in either wild-type mice or in
Stat5a/5b/ mice with near-normal
hematocrit. After administration of phenylhydrazine, the reticulocyte
count in wild-type mice increased sharply, reaching a maximum of
65.3% ± 1.7% (mean ± SEM) on day 6 (Figure 2). However, in
Stat5a/5b/ mice the maximal
reticulocyte count was only 28.4% ± 3.9%. By day 9, the
reticulocyte count in the wild-type mice had decreased to less than
10%, suggesting they had recovered from their blood loss and
down-regulated their erythropoietic response. In contrast, Stat5a/ 5b/ mice on day 9 still
maintained an elevated reticulocyte count of 28.4% ± 0.6%, clearly
showing they had not yet recovered from loss in red cell mass.
Therefore, Stat5a/5b/ mice with a
near-normal hematocrit at the basal state are deficient in generating
high erythropoietic rates and show a sluggish, blunted response to
erythropoietic stress.
Increased spleen size in
Stat5a /5b/ mice have a chronic,
persistent anemia (Figure 1), in the absence of continuous blood loss
or hemolysis. This suggests a defect in the Epo-mediated compensatory
feedback mechanism. We examined serum Epo levels in anemic
Stat5a/5b/ mice. Serum Epo in wild-type
mice was recently found to be in the range of 10 to 20 mU/mL.22 We found that, whereas wild-type and
Stat5a/5b/ mice with near-normal
hematocrits had a serum Epo concentration of less than 100 mU/mL,
anemic Stat5a/5b/ mice had serum Epo
levels that were grossly elevated, ranging between 360 and 12 000
mU/mL (Table 2). In the mouse, increased erythropoiesis in response to elevated Epo occurs principally in the
spleen,23,24 stimulating expansion of the spleen red pulp
and an increase in spleen size. We therefore examined spleen size in
Stat5a/5b/ mice. We found that the
spleen was enlarged up to 10 times the normal size in anemic
Stat5a/5b/ mice. Histologic examination
of enlarged spleens in anemic
Stat5a/5b/ mice shows marked expansion
of red pulp with predominantly erythroid extramedullary erythropoiesis.
There was also follicular hyperplasia of white pulp (Figure
3A). We found an inverse correlation
between spleen size and hematocrit or serum hemoglobin concentration
(Figure 3B). It is therefore likely that the increase in spleen size is primarily a compensatory response to anemia. Consistent with this, we
also found that enlarged spleens in
Stat5a/5b/ mice were first seen at 3.5 weeks of age (Figure 3B). This correlates with the developmental stage
at which growth rate in the mouse begins to slow down, erythropoietic
reserve becomes available, and some of the
Stat5a/5b/ mice begin to recover from
their neonatal anemia.
A block to erythroid differentiation at the early erythroblast
stage in Stat5a /5b/
mice. This raised the possibility that erythropoiesis in these mice,
although expanded, is ineffective. To examine this, we developed a flow
cytometry assay that allows quantitative assessment of the maturation
stage of differentiating erythroblasts in hematopoietic tissue (Figure
4). Epo signaling becomes essential
during terminal red cell differentiation. Several erythroid precursor
differentiation stages have been recognized and defined
morphologically, based on a gradual decrease in cell volume, increasing
chromatin condensation and increasing hemoglobinization as terminal
differentiation proceeds.25 These are, from least to most
differentiated, the proerythroblasts, the basophilic and
polychromatophilic erythroblasts, and the orthochromatophilic erythroblasts, which give rise to reticulocytes by enucleation (Figure
4). The cell-surface erythroid-specific Ter119 antigen is expressed by
terminally differentiating erythroblasts26,27 and is
closely associated with murine glycophorin A.27,28 We found that it is first expressed at intermediate levels at the proerythroblast stage. All erythroid precursors subsequent to the
proerythroblast stage express Ter119 at high levels. Conversely, the
transferrin receptor (CD71), though not erythroid-specific, is
expressed at very high levels by early erythroid precursors, principally proerythroblasts and early basophilic
erythroblasts,29 and its levels decrease with erythroid
maturation. We immunostained cells from spleen or bone marrow
simultaneously for Ter119 and CD71. Using flow cytometry, we defined 4 cell populations with specific staining characteristics:
Ter119medCD71high,
Ter119highCD71high,
Ter119highCD71med, and
Ter119highCD71low (Figure 4, regions
I-IV, respectively). Cells from each of these populations were sorted
and analyzed morphologically. The morphologic characteristics broadly
corresponded to proerythroblasts in the Ter119medCD71high cell population (Figure 4B,
region I), basophilic erythroblasts in the
Ter119highCD71high cell population (Figure 4B,
region II), late basophilic and polychromatophilic erythroblasts in the
Ter119highCD71med cell population (Figure 4B,
region III), and orthochromatophilic erythroblasts in the
Ter119highCD71low cell population (Figure 4B,
region IV). Erythroblasts sorted from regions III and IV are all
positive for hemoglobin expression, as judged by positive staining for
diaminobenzidine (data not shown). Therefore, simultaneous
immunostaining for Ter119 and CD71 allows flow cytometric
identification of erythroblasts as they proceed through terminal
differentiation in hematopoietic tissue. Although the relative number
of cells in each of these populations varied somewhat between mice, it
was very similar for a given mouse, regardless of whether hematopoietic
cells were derived from bone marrow or from spleen (data not
shown).
We used this assay to quantitatively analyze erythroid precursors in
anemic Stat5a
We looked at whether the altered Ter119/CD71 FACS profile in
Stat5a We next examined whether the dramatic increase in ratio of early to
late erythroblasts in Stat5a Thus, our findings show that there is a significant delay in
progression of early to late erythroblasts in
Stat5a Increased apoptosis in early erythroblasts of anemic
Stat5a /5b/ mice. We immunolabeled bone
marrow and spleen cells for CD71 and Ter119 and then incubated the
cells with annexin V and propidium iodide (Figure
6). Dead cells with
leaky plasma membranes label positive for propidium iodide and were
excluded from further analysis. Cells that have entered the apoptotic
program label positive for annexin V but remain negative for propidium
iodide. We found a 20-fold increase in the total number of cells
positive for annexin V in Stat5a/5b/
bone marrow: 8% of Stat5a/5b/
Ter119-positive bone marrow cells were annexin V-positive, compared with 0.4% of wild-type Ter119-positive bone marrow cells (Figure 6).
Further, increased apoptosis was principally seen in the early erythroblast population (Ter119highCD71high
cells). Therefore, decreased survival of early erythroblasts may
account, at least in part, for the apparent block in their differentiation into late erythroblasts. A similar examination of
apoptotic rates in bone marrow erythroblasts of the tissue-specific VHL/ mice did not show increased apoptosis (data not
shown). Therefore, the increased rate of apoptosis in
Stat5a/5b/ erythroblasts is not a
result of splenomegaly or of increased erythropoiesis per se. Despite a
clear increase in apoptosis of Stat5a/5b/ bone marrow erythroblasts,
we could not detect annexin V binding in spleen erythroblasts. This may
be due to more efficient clearance of apoptotic cells in adult
spleen.31 Significant levels of apoptosis were
detected in neonatal spleens from
Stat5a/5b/ mice (see
below).
Decreased bcl-xL expression in
Stat5a
We next used the flow cytometric measurement of bcl-xL to
look at its expression in adult spleen early erythroblasts. We found a clear reduction of bcl-xL levels in early
erythroblasts of anemic adult
Stat5a Neonatal spleen erythropoiesis: apoptosis and reduced
bcl-xL expression in
Stat5a /5b/ mice showed an increase in
the number of cells with immature morphology (Figure
8A). On flow cytometry analysis, we found
that wild-type fetal and neonatal hematopoietic tissues contained
relatively larger pools of proerythroblasts and early erythroblasts
compared with adult hematopoietic tissue (Figure 8B and data not
shown). Figure 8 shows representative flow cytometry analysis on
neonatal spleen cells. The ratio of early to late erythroblasts in the Stat5a/5b/ neonatal spleen is elevated
compared to that of wild-type neonates, but not as dramatically as in
adult Stat5a/5b/ hematopoietic tissue.
Presumably this is, in part, due to decreased ability to mount a
compensatory increase in early erythroblast numbers. The most striking
abnormality in the neonatal spleens is a substantial increase in
annexin V binding in Stat5a/5b/
erythroblasts throughout terminal differentiation (Figure 8C). The
largest increase in apoptosis is seen in early
Stat5a/5b/ erythroblasts (region II,
Ter119highCD71high), where there is a 13-fold
increase in annexin V+ cells compared with control.
Apoptosis is also clearly increased at later stages of
differentiation (regions III and IV). The increased apoptosis throughout terminal differentiation in
Stat5a/5b/ neonatal
erythroblasts may also account for the relatively preserved ratio of
early to late erythroblasts when compared with the adult, where
apoptosis was primarily confined to early
Stat5a/5b/ erythroblasts.
In addition to increased apoptosis, expression of the erythroid
differentiation marker Ter119 is also reduced, substantially in some
neonates (Figure 8B, Stat5a We measured the level of bcl-xL expression in
representative 3-day-old neonates from 2 litters analyzed in the same
experiment (Figure 9). This showed that
expression of bcl-xL is reduced in neonatal spleen from
Stat5a
Stimulation of EpoR leads to the rapid activation of Stat5, one of
several signals emanating from the EpoR.32 We evaluated the role of Stat5 in EpoR function in vivo by studying
Stat5a We investigated the cellular deficit underlying the erythropoietic
phenotype of Stat5a Quantitative analysis by flow cytometry of hematopoietic tissue from
anemic adult Stat5a The decreased expression of bcl-xL in
Stat5a
Although a subgroup of adult Stat5a Stress erythropoiesis occurs in the mouse spleen. We found that anemic
Stat5a Enlarged spleens in Stat5a Our findings identify the early erythroblast
(CD71highTer119high) as a principal target of
EpoR and Stat5 signaling. EpoR is first expressed by very early
erythroid progenitors (erythroid burst-forming unit), and its
expression is down-regulated following the late basophilic erythroblast
stage.44,45 This suggests it may potentially act during
multiple stages of erythroid differentiation. The principal target cell
thought to be regulated by Epo is the erythroid colony-forming unit
(CFU-E), a cell giving rise to differentiated red cells within 5 to 6 generations.46,47 The EpoR The mechanisms allowing EpoR to modulate erythropoietic rate in
response to stress are largely unknown. A long-standing hypothesis suggests that erythropoietic rate may depend on the fraction of erythroid progenitors rescued from apoptosis by
EpoR.23,33,47 The close correlation between early
erythroblast survival and erythropoietic rate in
Stat5a The work presented here suggests that in vivo analysis of EpoR signaling may shed light on the homeostatic mechanisms regulating stress erythropoiesis, as well as on possible deficits in syndromes of disrupted red blood cell production.
We thank Drs Stefan Constantinescu and Lily Huang for helpful
discussion, Glen Pardis for help with flow cytometry, Jeanne Reis for
technical help and Dr J. N. Ihle (St Jude Children's Research
Hospital, Memphis, TN) for permission to use the
Stat5a
Submitted March 8, 2001; accepted July 18, 2001.
Supported by grant HL 32262 from the National Institutes of Health and by a grant from Amgen (H.F.L.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Harvey F. Lodish, Whitehead Institute for Biomedical Research, 9 Cambridge Ctr, Cambridge, MA 02142; e-mail: lodish{at}wi.mit.edu.
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A. Diwan, A. G. Koesters, A. M. Odley, S. Pushkaran, C. P. Baines, B. T. Spike, D. Daria, A. G. Jegga, H. Geiger, B. J. Aronow, et al. Unrestrained erythroblast development in Nix-/- mice reveals a mechanism for apoptotic modulation of erythropoiesis PNAS, April 17, 2007; 104(16): 6794 - 6799. [Abstract] [Full Text] [PDF]
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M. Maetens, G. Doumont, S. D. Clercq, S. Francoz, P. Froment, E. Bellefroid, U. Klingmuller, G. Lozano, and J.-C. Marine Distinct roles of Mdm2 and Mdm4 in red cell production Blood, March 15, 2007; 109(6): 2630 - 2633. [Abstract] [Full Text] [PDF]
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H. Y. Mukai, H. Motohashi, O. Ohneda, N. Suzuki, M. Nagano, and M. Yamamoto Transgene Insertion in Proximity to thec-myb Gene Disrupts Erythroid-Megakaryocytic Lineage Bifurcation Mol. Cell. Biol., November 1, 2006; 26(21): 7953 - 7965. [Abstract] [Full Text] [PDF]
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K. E. Jie, M. C. Verhaar, M.-J. M. Cramer, K. van der Putten, C. A. J. M. Gaillard, P. A. Doevendans, H. A. Koomans, J. A. Joles, and B. Braam Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors Am J Physiol Renal Physiol, November 1, 2006; 291(5): F932 - F944. [Abstract] [Full Text] [PDF]
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S. Hosoya-Ohmura, N. Mochizuki, M. Suzuki, O. Ohneda, K. Ohneda, and M. Yamamoto GATA-4 Incompletely Substitutes for GATA-1 in Promoting Both Primitive and Definitive Erythropoiesis in Vivo J. Biol. Chem., October 27, 2006; 281(43): 32820 - 32830. [Abstract] [Full Text] [PDF]
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G. Lee, A. Lo, S. A. Short, T. J. Mankelow, F. Spring, S. F. Parsons, K. Yazdanbakhsh, N. Mohandas, D. J. Anstee, and J. A. Chasis Targeted gene deletion demonstrates that the cell adhesion molecule ICAM-4 is critical for erythroblastic island formation Blood, September 15, 2006; 108(6): 2064 - 2071. [Abstract] [Full Text] [PDF]
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G. Bungartz, S. Stiller, M. Bauer, W. Muller, A. Schippers, N. Wagner, R. Fassler, and C. Brakebusch Adult murine hematopoiesis can proceed without beta1 and beta7 integrins Blood, September 15, 2006; 108(6): 1857 - 1864. [Abstract] [Full Text] [PDF]
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G. J. Spangrude, S. Cho, O. Guedelhoefer, R. C. VanWoerkom, and W. H. Fleming Mouse Models of Hematopoietic Engraftment: Limitations of Transgenic Green Fluorescent Protein Strains and a High-Performance Liquid Chromatography Approach to Analysis of Erythroid Chimerism Stem Cells, September 1, 2006; 24(9): 2045 - 2051. [Abstract] [Full Text] [PDF]
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L. Garcon, C. Rivat, C. James, C. Lacout, V. Camara-Clayette, V. Ugo, Y. Lecluse, A. Bennaceur-Griscelli, and W. Vainchenker Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells Blood, September 1, 2006; 108(5): 1551 - 1554. [Abstract] [Full Text] [PDF]
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V. G. Karur, C. A. Lowell, P. Besmer, V. Agosti, and D. M. Wojchowski Lyn kinase promotes erythroblast expansion and late-stage development Blood, September 1, 2006; 108(5): 1524 - 1532. [Abstract] [Full Text] [PDF]
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B. Dumitriu, M. R. Patrick, J. P. Petschek, S. Cherukuri, U. Klingmuller, P. L. Fox, and V. Lefebvre Sox6 cell-autonomously stimulates erythroid cell survival, proliferation, and terminal maturation and is thereby an important enhancer of definitive erythropoiesis during mouse development Blood, August 15, 2006; 108(4): 1198 - 1207. [Abstract] [Full Text] [PDF]
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H. Sakamoto, G. Dai, K. Tsujino, K. Hashimoto, X. Huang, T. Fujimoto, M. Mucenski, J. Frampton, and M. Ogawa Proper levels of c-Myb are discretely defined at distinct steps of hematopoietic cell development Blood, August 1, 2006; 108(3): 896 - 903. [Abstract] [Full Text] [PDF]
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K. M. Kinross, A. J. Clark, R. M. Iazzolino, and P. O. Humbert E2f4 regulates fetal erythropoiesis through the promotion of cellular proliferation Blood, August 1, 2006; 108(3): 886 - 895. [Abstract] [Full Text] [PDF]
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M. Suzuki, K. Ohneda, S. Hosoya-Ohmura, S. Tsukamoto, O. Ohneda, S. Philipsen, and M. Yamamoto Real-time monitoring of stress erythropoiesis in vivo using Gata1 and beta-globin LCR luciferase transgenic mice Blood, July 15, 2006; 108(2): 726 - 733. [Abstract] [Full Text] [PDF]
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Y. Liu, R. Pop, C. Sadegh, C. Brugnara, V. H. Haase, and M. Socolovsky Suppression of Fas-FasL coexpression by erythropoietin mediates erythroblast expansion during the erythropoietic stress response in vivo Blood, July 1, 2006; 108(1): 123 - 133. [Abstract] [Full Text] [PDF]
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A. Vegiopoulos, P. Garcia, N. Emambokus, and J. Frampton Coordination of erythropoiesis by the transcription factor c-Myb Blood, June 15, 2006; 107(12): 4703 - 4710. [Abstract] [Full Text] [PDF]
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T. Ragoczy, M.A. Bender, A. Telling, R. Byron, and M. Groudine The locus control region is required for association of the murine beta-globin locus with engaged transcription factories during erythroid maturation Genes & Dev., June 1, 2006; 20(11): 1447 - 1457. [Abstract] [Full Text] [PDF]
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B. Li, N. Jia, R. Kapur, and K. T. Chun Cul4A targets p27 for degradation and regulates proliferation, cell cycle exit, and differentiation during erythropoiesis Blood, June 1, 2006; 107(11): 4291 - 4299. [Abstract] [Full Text] [PDF]
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T. Katsumoto, Y. Aikawa, A. Iwama, S. Ueda, H. Ichikawa, T. Ochiya, and I. Kitabayashi MOZ is essential for maintenance of hematopoietic stem cells. Genes & Dev., May 15, 2006; 20(10): 1321 - 1330. [Abstract] [Full Text] [PDF]
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H. M. Rooke and S. H. Orkin Phosphorylation of Gata1 at serine residues 72, 142, and 310 is not essential for hematopoiesis in vivo Blood, May 1, 2006; 107(9): 3527 - 3530. [Abstract] [Full Text] [PDF]
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K. Wagner, P. Zhang, F. Rosenbauer, B. Drescher, S. Kobayashi, H. S. Radomska, J. L. Kutok, D. G. Gilliland, J. Krauter, and D. G. Tenen Absence of the transcription factor CCAAT enhancer binding protein {alpha} results in loss of myeloid identity in bcr/abl-induced malignancy PNAS, April 18, 2006; 103(16): 6338 - 6343. [Abstract] [Full Text] [PDF]
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T. Ito, N. Arimitsu, M. Takeuchi, N. Kawamura, M. Nagata, K. Saso, N. Akimitsu, H. Hamamoto, S. Natori, A. Miyajima, et al. Transcription Elongation Factor S-II Is Required for Definitive Hematopoiesis Mol. Cell. Biol., April 15, 2006; 26(8): 3194 - 3203. [Abstract] [Full Text] [PDF]
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M. P. Menon, J. Fang, and D. M. Wojchowski Core erythropoietin receptor signals for late erythroblast development Blood, April 1, 2006; 107(7): 2662 - 2672. [Abstract] [Full Text] [PDF]
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M. Um and H. F. Lodish Antiapoptotic Effects of Erythropoietin in Differentiated Neuroblastoma SH-SY5Y Cells Require Activation of Both the STAT5 and AKT Signaling Pathways J. Biol. Chem., March 3, 2006; 281(9): 5648 - 5656. [Abstract] [Full Text] [PDF]
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A. D. Patterson, M. C. Hollander, G. F. Miller, and A. J. Fornace Jr. Gadd34 requirement for normal hemoglobin synthesis. Mol. Cell. Biol., March 1, 2006; 26(5): 1644 - 1653. [Abstract] [Full Text] [PDF]
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 J. F. Langenheim, D. Tan, A. M. Walker, and W. Y. Chen Two Wrongs Can Make a Right: Dimers of Prolactin and Growth Hormone Receptor Antagonists Behave as Agonists Mol. Endocrinol., March 1, 2006; 20(3): 661 - 674. [Abstract] [Full Text] [PDF]
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K. Kitajima, M. Tanaka, J. Zheng, H. Yen, A. Sato, D. Sugiyama, H. Umehara, E. Sakai, and T. Nakano Redirecting differentiation of hematopoietic progenitors by a transcription factor, GATA-2 Blood, March 1, 2006; 107(5): 1857 - 1863. [Abstract] [Full Text] [PDF]
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M. Sanchez, I. L. Weissman, M. Pallavicini, M. Valeri, P. Guglielmelli, A. M. Vannucchi, G. Migliaccio, and A. R. Migliaccio Differential Amplification of Murine Bipotent Megakaryocytic/Erythroid Progenitor and Precursor Cells During Recovery from Acute and Chronic Erythroid Stress Stem Cells, February 1, 2006; 24(2): 337 - 348. [Abstract] [Full Text] [PDF]
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J. M. Brown, J. Leach, J. E. Reittie, A. Atzberger, J. Lee-Prudhoe, W. G. Wood, D. R. Higgs, F. J. Iborra, and V. J. Buckle Coregulated human globin genes are frequently in spatial proximity when active J. Cell Biol., January 17, 2006; 172(2): 177 - 187. [Abstract] [Full Text] [PDF]
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J. Zheng, K. Kitajima, E. Sakai, T. Kimura, N. Minegishi, M. Yamamoto, and T. Nakano Differential effects of GATA-1 on proliferation and differentiation of erythroid lineage cells Blood, January 15, 2006; 107(2): 520 - 527. [Abstract] [Full Text] [PDF]
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T. Ishikawa-Sekigami, Y. Kaneko, H. Okazawa, T. Tomizawa, J. Okajo, Y. Saito, C. Okuzawa, M. Sugawara-Yokoo, U. Nishiyama, H. Ohnishi, et al. SHPS-1 promotes the survival of circulating erythrocytes through inhibition of phagocytosis by splenic macrophages Blood, January 1, 2006; 107(1): 341 - 348. [Abstract] [Full Text] [PDF]
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F. Martelli, B. Ghinassi, B. Panetta, E. Alfani, V. Gatta, A. Pancrazzi, C. Bogani, A. M. Vannucchi, F. Paoletti, G. Migliaccio, et al. Variegation of the phenotype induced by the Gata1low mutation in mice of different genetic backgrounds Blood, December 15, 2005; 106(13): 4102 - 4113. [Abstract] [Full Text] [PDF]
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C. J. Wu, L. Krishnamurti, J. L. Kutok, M. Biernacki, S. Rogers, W. Zhang, J. H. Antin, and J. Ritz Evidence for ineffective erythropoiesis in severe sickle cell disease Blood, November 15, 2005; 106(10): 3639 - 3645. [Abstract] [Full Text] [PDF]
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L. Silberstein, M.-J. Sanchez, M. Socolovsky, Y. Liu, G. Hoffman, S. Kinston, S. Piltz, M. Bowen, L. Gambardella, A. R. Green, et al. Transgenic Analysis of the Stem Cell Leukemia +19 Stem Cell Enhancer in Adult and Embryonic Hematopoietic and Endothelial Cells Stem Cells, September 1, 2005; 23(9): 1378 - 1388. [Abstract] [Full Text] [PDF]
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M. M. Rhodes, P. Kopsombut, M. C. Bondurant, J. O. Price, and M. J. Koury Bcl-xL prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin Blood, September 1, 2005; 106(5): 1857 - 1863. [Abstract] [Full Text] [PDF]
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M. A. Hall, N. J. Slater, C. G. Begley, J. M. Salmon, L. J. Van Stekelenburg, M. P. McCormack, S. M. Jane, and D. J. Curtis Functional but Abnormal Adult Erythropoiesis in the Absence of the Stem Cell Leukemia Gene Mol. Cell. Biol., August 1, 2005; 25(15): 6355 - 6362. [Abstract] [Full Text] [PDF]
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 M. Pesu, J. O'Shea, L. Hennighausen, and O. Silvennoinen Identification of an Acquired Mutation in Jak2 Provides Molecular Insights into the Pathogenesis of Myeloproliferative Disorders Mol. Interv., August 1, 2005; 5(4): 211 - 215. [Abstract] [Full Text] [PDF]
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W. Tong, J. Zhang, and H. F. Lodish Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways Blood, June 15, 2005; 105(12): 4604 - 4612. [Abstract] [Full Text] [PDF]
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R. Doyonnas, J. S. Nielsen, S. Chelliah, E. Drew, T. Hara, A. Miyajima, and K. M. McNagny Podocalyxin is a CD34-related marker of murine hematopoietic stem cells and embryonic erythroid cells Blood, June 1, 2005; 105(11): 4170 - 4178. [Abstract] [Full Text] [PDF]
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 C. Angelin-Duclos, C. Domenget, A. Kolbus, H. Beug, P. Jurdic, and J. Samarut Thyroid hormone T3 acting through the thyroid hormone {alpha} receptor is necessary for implementation of erythropoiesis in the neonatal spleen environment in the mouse Development, March 1, 2005; 132(5): 925 - 934. [Abstract] [Full Text] [PDF]
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G. Terszowski, C. Waskow, P. Conradt, D. Lenze, J. Koenigsmann, D. Carstanjen, I. Horak, and H.-R. Rodewald Prospective isolation and global gene expression analysis of the erythrocyte colony-forming unit (CFU-E) Blood, March 1, 2005; 105(5): 1937 - 1945. [Abstract] [Full Text] [PDF]
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A. L. Drayer, A.-K. Boer, E. L. Los, M. T. Esselink, and E. Vellenga Stem Cell Factor Synergistically Enhances Thrombopoietin-Induced STAT5 Signaling in Megakaryocyte Progenitors through JAK2 and Src Kinase Stem Cells, February 1, 2005; 23(2): 240 - 251. [Abstract] [Full Text] [PDF]
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A. Halupa, M. L. Bailey, K. Huang, N. N. Iscove, D. E. Levy, and D. L. Barber A novel role for STAT1 in regulating murine erythropoiesis: deletion of STAT1 results in overall reduction of erythroid progenitors and alters their distribution Blood, January 15, 2005; 105(2): 552 - 561. [Abstract] [Full Text] [PDF]
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 M. Nakano, K. Ohneda, H. Yamamoto-Mukai, R. Shimizu, O. Ohneda, S. Ohmura, M. Suzuki, S. Tsukamoto, T. Yanagawa, H. Yoshida, et al. Transgenic over-expression of GATA-1 mutant lacking N-finger domain causes hemolytic syndrome in mouse erythroid cells Genes Cells, January 1, 2005; 10(1): 47 - 62. [Abstract] [Full Text] [PDF]
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K. W. Harder, C. Quilici, E. Naik, M. Inglese, N. Kountouri, A. Turner, K. Zlatic, D. M. Tarlinton, and M. L. Hibbs Perturbed myelo/erythropoiesis in Lyn-deficient mice is similar to that in mice lacking the inhibitory phosphatases SHP-1 and SHIP-1 Blood, December 15, 2004; 104(13): 3901 - 3910. [Abstract] [Full Text] [PDF]
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Y. Nakano, S. Imagawa, K. Matsumoto, C. Stockmann, N. Obara, N. Suzuki, T. Doi, T. Kodama, S. Takahashi, T. Nagasawa, et al. Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity, and restores indicators in an in vivo mouse model of anemia of chronic disease Blood, December 15, 2004; 104(13): 4300 - 4307. [Abstract] [Full Text] [PDF]
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J. J. Schuringa, K. Wu, G. Morrone, and M. A.S. Moore Enforced Activation of STAT5A Facilitates the Generation of Embryonic Stem-Derived Hematopoietic Stem Cells That Contribute to Hematopoiesis In Vivo Stem Cells, December 1, 2004; 22(7): 1191 - 1204. [Abstract] [Full Text] [PDF]
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Y. Cui, G. Riedlinger, K. Miyoshi, W. Tang, C. Li, C.-X. Deng, G. W. Robinson, and L. Hennighausen Inactivation of Stat5 in Mouse Mammary Epithelium during Pregnancy Reveals Distinct Functions in Cell Proliferation, Survival, and Differentiation Mol. Cell. Biol., September 15, 2004; 24(18): 8037 - 8047. [Abstract] [Full Text] [PDF]
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C. Waskow, G. Terszowski, C. Costa, M. Gassmann, and H.-R. Rodewald Rescue of lethal c-KitW/W mice by erythropoietin Blood, September 15, 2004; 104(6): 1688 - 1695. [Abstract] [Full Text] [PDF]
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J. J. Schuringa, K. Y. Chung, G. Morrone, and M. A.S. Moore Constitutive Activation of STAT5A Promotes Human Hematopoietic Stem Cell Self-Renewal and Erythroid Differentiation J. Exp. Med., September 7, 2004; 200(5): 623 - 635. [Abstract] [Full Text] [PDF]
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 R. M. Teague, R. M. Tempero, S. Thomas, K. Murali-Krishna, and B. H. Nelson Proliferation and Differentiation of CD8+ T Cells in the Absence of IL-2/15 Receptor {beta}-Chain Expression or STAT5 Activation J. Immunol., September 1, 2004; 173(5): 3131 - 3139. [Abstract] [Full Text] [PDF]
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S. M. Jacobs-Helber and S. T. Sawyer Jun N-terminal kinase promotes proliferation of immature erythroid cells and erythropoietin-dependent cell lines Blood, August 1, 2004; 104(3): 696 - 703. [Abstract] [Full Text] [PDF]
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W. Zhou, Q. Zhao, R. Sutton, H. Cumming, X. Wang, L. Cerruti, M. Hall, R. Wu, J. M. Cunningham, and S. M. Jane The Role of p22 NF-E4 in Human Globin Gene Switching J. Biol. Chem., June 18, 2004; 279(25): 26227 - 26232. [Abstract] [Full Text] [PDF]
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E. van den Akker, T. van Dijk, M. Parren-van Amelsvoort, K. S. Grossmann, U. Schaeper, K. Toney-Earley, S. E. Waltz, B. Lowenberg, and M. von Lindern Tyrosine kinase receptor RON functions downstream of the erythropoietin receptor to induce expansion of erythroid progenitors Blood, June 15, 2004; 103(12): 4457 - 4465. [Abstract] [Full Text] [PDF]
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K.-H. Chang, M. Tam, and M. M. Stevenson Inappropriately low reticulocytosis in severe malarial anemia correlates with suppression in the development of late erythroid precursors Blood, May 15, 2004; 103(10): 3727 - 3735. [Abstract] [Full Text] [PDF]
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H. Beauchemin, M.-J. Blouin, and M. Trudel Differential Regulatory and Compensatory Responses in Hematopoiesis/Erythropoiesis in {alpha}- and {beta}-Globin Hemizygous Mice J. Biol. Chem., May 7, 2004; 279(19): 19471 - 19480. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
