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HEMATOPOIESIS
From the Gladstone Institute of Virology and
Immunology, Departments of Microbiology and Immunology, Pathology, and
Medicine, University of California at San Francisco, San Francisco, CA.
The transcription factor signal transducers and activators of
transcription 5 (STAT5) is activated by numerous cytokines that orchestrate blood cell development. Multilineage peripheral blood cytopenias were observed in adult mice lacking both isoforms of STAT5
(STAT5A and STAT5B) as well as accelerated rates of apoptosis in the
bone marrow. Although the hematopoietic stem cell (HSC) population was
preserved in a number of these mice, the post-HSC progenitor
populations were diminished and a marked reduction in functional
progenitors (spleen colony-forming units) was detected. Competitive
bone marrow transplantation studies in vivo revealed a profound
impairment of repopulation potential of STAT5-null HSCs, leading to
complete lack of contribution to the myeloid, erythroid, and lymphoid
lineages. These abnormalities were associated with heightened
proliferation activity in the HSC fraction, suggesting the action of
homeostatic mechanisms to maintain sufficient levels of diverse blood
cell types for viability. Thus, STAT5 normally sustains the robust
hematopoietic reserve that contributes to host viability through
crucial survival effects on early progenitor cells.
(Blood. 2002;99:95-101) Hematolymphoid development is a complex process
controlled by multiple positive and negative regulatory systems to
maintain homeostasis. This process begins with hematopoietic stem cells (HSCs), which possess a high proliferative capacity, a differentiative potential encompassing all hematopoietic lineages, and the ability to
repopulate the hematopoietic system of a bone marrow-ablated animal
for its lifespan. In response to unknown signals, HSCs undergo a
differentiation program, yielding cells that have short-term repopulating activity. These cells subsequently give rise to
multilineage progenitors that are restricted to either the myeloid
(common myeloid progenitor, or CMP) or lymphoid (common lymphoid
progenitor, or CLP) lineages.1,2 Lineage-specific
differentiation of these pluripotent cells and further expansion
produces mature cells of a given lineage.3
Cytokines that use class I cytokine receptors play an indispensable
role in controlling hematopoietic development and function. Many of
these cytokines act on the HSCs themselves, such as granulocyte colony-stimulating factor (G-CSF), interleukin-6 (IL-6), IL-11, thrombopoietin (TPO), and leukemia-inhibitory factor.4
Others, such as erythropoietin, TPO, and G-CSF, act on
lineage-committed progenitors exclusively or in addition to their
earlier effects.5-7 How this family of receptors generates
specificity in biologic outcomes while employing shared intracellular
signaling pathways has been a point of considerable interest. The
discovery of the JAK-STAT pathway appeared to offer one mechanism
through which cytokine receptors could selectively up-regulate distinct
target genes and be responsible for specific biologic behaviors. STATs are cytoplasmically located, latent transcription factors that dimerize
on phosphorylation by an activated receptor complex, translocate into
the nucleus, and increase the transcription of target genes by binding
to specific DNA sequence motifs.8,9 Various genes have
been shown to be up-regulated by STAT molecules, including those
involved in cell cycle progression, antiapoptosis, and regulation of
cytokine signaling.10
One member of the STAT family, STAT5, is activated by diverse cytokine
receptors involved at multiple levels within the hematopoietic system.
The widespread engagement of its 2 isoforms, STAT5A and STAT5B, has
implicated STAT5 as a potentially important component of cytokine
receptor signaling in this tissue. Cell culture studies have suggested
a possible role for STAT5 in hematolymphoid development. For example,
STAT5 was shown to be involved in erythropoietin-induced proliferation
of TF-1 cells.11 STAT5 has also been implicated in both
the IL-3-induced proliferation and G-CSF-induced differentiation in
32D cells.12 Surprisingly, therefore, mice deficient in
either STAT5A13 or STAT5B14 were found to
exhibit dramatic defects in specific nonhematopoietic tissues, but only
subtle alterations in the regulation of hematopoietic
cells.15-17 Moreover, mice deficient in both the STAT5A
and STAT5B isoforms were reported to have no further defects in the
production of mature blood cells of various lineages with the exception
of decreased numbers of peripheral T cells.18 However,
some evidence of additional hematologic dysregulation was evident in
these animals, such as reduced bone marrow colony counts in vitro and
notable extramedullary hematopoiesis.18,19 In addition,
marked fetal anemia in vivo as well as defects in erythropoietin-dependent production and survival of fetal liver hematopoietic colonies in vitro were subsequently
reported.20 Finally, an increase in apoptosis of cultured
STAT5A/5B-deficient bone marrow progenitors in the presence of
granulocyte-macrophage colony-stimulating factor was also
described.21
In view of these provocative findings and the fact that compensatory
mechanisms may mask the biologic action of a particular molecular
component in vivo, we examined the hematologic status of
STAT5A/5B-deficient mice in depth. Our studies uncovered an important
role for STAT5 in hematopoiesis at an early progenitor stage in vivo.
In these mice, marked impairment in hematopoietic potential affecting
diverse blood lineages is linked to significant abnormalities in
central and peripheral hematolymphoid tissues.
Handling and characterization of mice
Flow cytometry
Bone marrow transfer studies Recipient mice were 8-week-old sex-matched C57Bl/6 obtained from Jackson Laboratories (Bar Harbor, ME). Recipients were -irradiated from a Cesium source in two 450-rad doses 4 to 5 hours apart. Spleen
colony-forming unit (CFU-S) studies were performed as previously described.23 Briefly, whole bone marrow cells from donor
mice were injected via tail vein, spleens were harvested 8 or 12 days after transfer, and macroscopic colonies were enumerated. Mice receiving the transplants were maintained on 2.5 mg/100 mL Sulfatrim Pediatric Suspension (Alpharma, Baltimore, MD). Competitive
repopulation studies were performed as previously
described.24 LindimSca-1+ tester
cells (CD45.2+), derived from wild-type littermate or
STAT5A/5B / whole bone marrow, were sorted by using
antibodies to Sca-1 and Ter-119, Gr-1, CD3, B220, and CD11b. Competitor
whole bone marrow from congenic B6.SLJ (CD45.1+) mice was
harvested as above. Tester and competitor cells were mixed at various
ratios (see "Inferior competitive repopulating capacity of
STAT5A/5B-deficient HSCs") and injected into irradiated recipients,
prepared as above. After 8 to 10 weeks, chimeric mice were killed, and
peripheral blood, spleen, thymus, and bone marrow were collected and
analyzed by FACS for contribution of CD45.1+- and
CD45.2+-derived cells to selected lineages.
Homing assay Cell labeling with 5- and 6-carboxyfluorescein diacetate succinimidyl ester (CSFE) was performed as described previously.25 Briefly, whole bone marrow from donor mice was labeled in PBS at a final concentration of 15 µM CSFE (Molecular Probes). After 12 minutes at 37°C, further dye uptake was prevented by adding a quarter volume of fetal bovine serum. Cells were washed twice with PBS, and 5 × 106 CFSE-labeled cells were injected into the tail vein of recipient mice that had been irradiated 18 hours before injection. Bone marrow was harvested 23 hours after injection, stained with lineage markers and Sca-1 as before, and the number of CFSE+ cells in each subset was enumerated by FACS.Statistical analysis Data are presented as mean ± SEM. Statistical significance was assessed by 2-sided Student t test.
Adult STAT5A/5B-deficient mice exhibit cytopenias affecting multiple peripheral blood lineages We characterized the peripheral blood compartment of adult STAT5A/5B-deficient mice and found significant abnormalities in multiple blood lineages. At 8 weeks of age, STAT5A/5B/
mice exhibited significantly decreased numbers of erythrocytes in
peripheral blood compared with wild-type littermate controls (Figure
1A). Platelets, a second myeloid lineage,
were also reduced in these mice, although this effect was less profound
(Figure 1B). A marked decrease in lymphocyte number in peripheral blood was also observed (Figure 1C); both T cells and B cells were decreased in STAT5A/5B-deficient animals (data not shown). Finally, although no
significant difference in peripheral neutrophil counts was detected
(Figure 1D), we observed a significant reduction in mature neutrophils
(Gr-1hi) in the bone marrow (see below). Thus, the absence
of STAT5A/5B was associated with abnormalities in multiple blood
cell lineages.
STAT5A/5B-deficient mice have hypocellular bone marrow and a defect within early progenitor cells Such broad defects in peripheral blood cell numbers in STAT5A/5B-deficient mice could be due to accelerated peripheral consumption or destruction of mature cells, to a lowered capacity to produce mature cells, or to a combination of these 2 mechanisms. The multilineage character of the effects we observed suggested that a primary pathophysiologic defect might be in the bone marrow, where both unique and shared precursors for these cell types exist. Gross examination of bone marrow in STAT5A/5B-deficient mice revealed generalized hypocellularity compared with wild-type mice (Figure 2A). This 2-fold decrease in total nucleated cells in the bone is consistent with the hypothesis that a central defect in the bone marrow is responsible for the pancytopenia observed in the periphery.
Various cytokines that trigger STAT5 activity are critical for the regulation of hematopoiesis at all levels of differentiation, including stem cells, multipotent progenitors, lineage-committed progenitors, and mature blood cells. We therefore sought to determine the specific developmental stage(s) in which the functional effects of STAT5 are manifested in the bone marrow. We used FACS analysis to subset bone marrow cells by expression of canonical surface lineage-defining markers (lin) and Sca-1 (Figure 2B). The HSCs, which are defined as cells that have both the capacity for self-renewal and the ability to reconstitute the multilineage hematopoietic system, are found within the lindimSca-1+ fraction.26 This population was increased as a percentage of total nucleated bone marrow cells in STAT5A/B-deleted mice compared with controls but was unchanged in absolute terms (Figure 2C). In contrast, the lindimSca-1neg/lo population, containing CLPs,2 CMPs,1 and oligopotent progenitors, was dramatically decreased in STAT5A/5B-deficient animals (Figure 2D). Also, we observed that the absolute number of mature neutrophils (Gr-1hi) in the bone marrow was decreased (wild type = 12.5 × 106 ± 4.1 per 2 hind legs and knock-out = 5.5 × 106 ± 1.6 per 2 hind legs) as well as progenitors for neutrophils (Gr-1int) (wild type = 10.4 × 106 ± 3.0 per 2 hind legs and knock-out = 5.2 × 106 ± 1.1 per 2 hind legs), erythrocytes (Ter119+) (wild type = 6.6 × 106 ± 0.96 per 2 hind legs and knock-out = 3.3 × 106 ± 0.79 per 2 hind legs), and B cells (B220+) (wild type = 12.6 × 106 ± 2.1 per 2 hind legs and knock-out = 5.0 × 106 ± 0.71 per 2 hind legs). Therefore, the absence of STAT5A/5B results in a marked decrease in lindimSca-1neg/lo cells as well as in specific lineage marker-positive cells in the bone marrow despite preservation of the earlier lindimSca-1+ HSC. A number of short-term bone marrow transfer assays were performed to
assess the functional capabilities of bone marrow from the
STAT5A/5B-deficient mice. Lethally irradiated wild-type mice typically
die of hematopoietic failure between 7 and 18 days after irradiation
unless they are given new hematopoietic progenitors from a donor
animal. Therefore, one functional assay determines the radioprotective
ability of whole bone marrow from a donor mouse. A dose of
2.5 × 105 transplanted whole bone marrow cells from
wild-type littermate control mice provided radioprotection to 100% of
lethally irradiated recipient mice for 20 days (Figure
3A). In contrast, the same dose of whole
bone marrow from a STAT5A/5B-deficient donor provided radioprotection
to only 12.5% of recipient mice through the same period (Figure 3A),
demonstrating that these cells have markedly decreased reconstituting
capacity as indicated by radioprotective effects. To determine whether
this phenotype derives from defects in homing or in postengraftment
expansion and hematopoiesis, irradiated recipients were injected with
wild-type or STAT5A/5B-deficient whole bone marrow that had been
labeled with the membrane dye CFSE. We found that the number of
CFSE+ cells in the HSC-containing
lindim/Sca-1+ fraction that had homed to the
bone marrow after 23 hours was comparable when whole bone marrow from
either STAT5A/5B-deficient or wild-type littermate donors was injected
(Figure 3B).
A second, direct, functional assay for progenitor cells is the in vivo
CFU-S assay,23 in which macroscopic colonies in the spleens of irradiated recipients are counted 8 or 12 days after bone
marrow transfer.26 We detected a pronounced reduction in CFU-S (day 12) colonies per donor in the STAT5A/5B-deleted mice relative to wild-type littermate controls (Figure
4A), which indicates an abnormality in
the early pluripotent progenitors. We observed a similarly dramatic
decrease in CFU-S (day 8) per donor in STAT5A/5B
Bone marrow deficiency involves increased apoptosis, rather than decreased proliferation In principle, the cellular effects described might be caused by various mechanisms, including decreases in the rates of proliferation, survival, or differentiation of selected progenitor populations. We used cell labeling with Annexin-V in conjunction with a DNA dye, To-Pro, to measure rates of apoptosis in the bone marrow. The absence of STAT5A/5B was associated with an increase in the rate of apoptosis of unfractionated bone marrow (31.1% ± 2.65%) relative to wild type (17.6% ± 0.73%). This 2-fold increase in cell death was seen in both the lin+ population as well as the lindimSca-1neg/lo population (Figure 5A), whereas the lindimSca-1+ compartment showed only a modest increase in the rate of apoptosis (Figure 5A). To measure proliferation, we used ToPro in conjunction with cell surface markers to quantitate DNA content in bone marrow by using DNA content more than 2n as an indirect measure of the proportion of cells undergoing cell cycle. An insignificant increase in the proportion of cells with DNA content more than 2n was observed among the unfractionated whole bone marrow population of STAT5A/5B-deficient bone marrow (17.2% ± 1.79%) in comparison to the wild-type marrow (13.4% ± 1.01%). Lin+ cells likewise showed little change in proliferation activity in STAT5A/5B-deleted mice (Figure 5B). In contrast, both the early lindimSca-1neg/lo and the lindimSca-1+ subsets exhibited a 2-fold increase in the percentage of cells with DNA content more than 2n in STAT5A/5B-deficient mice (Figure 5B). Together, these findings provide evidence of globally decreased cellular survival (represented as increased apoptosis) in bone marrow cells in the absence of STAT5A/5B, with a concurrent increase in cellular proliferation among the least differentiated hematopoietic cells.
Inferior competitive repopulating capacity of STAT5A/5B-deficient HSCs A rigorous functional test of stem cell fitness is the competitive repopulation assay, which measures the capacity of "tester" HSCs to reconstitute the hematopoietic system of irradiated recipient mice in direct competition with wild-type "competitor" bone marrow cells.26,27 For the representative experiment shown, we injected 2500 lindimSca-1+ tester cells from STAT5A/5B-deficient mice or wild-type littermate control mice, carrying the CD45.2 allele, together with 2 × 105 whole bone marrow competitor cells derived from congenic mice carrying the CD45.1 allele. An additional control group received 2 × 105 whole bone marrow competitor cells alone to establish the level of ablation achieved by the irradiation regimen. After 10 weeks, peripheral blood, thymus, spleen, and bone marrow were harvested for analysis of hematopoietic lineages by using various antibodies to lineage markers and to the 2 alleles of CD45. At this ratio of input cells, which was weighted to favor tester cells, wild-type tester cells (CD45.2+) gave rise to approximately 80% of all cellular lineages in all tissues examined, including Gr-1+ (Figure 6), and other specific lineages within peripheral blood, including T cells (CD3+) and B cells (B220+) (Figure 6A). As is commonly observed, residual radioresistant CD3+ T cells from the recipient mouse are detected in all groups, including those mice that received competitor cells alone (Figure 7A). Likewise, bone marrow cells representing the granulocyte (Gr-1+), B-cell (B220+), megakaryocyte (CD41+) lineages, and erythroid progenitors (Ter-119+), as well as thymocytes (CD3+), were predominantly CD45.2+ (Figure 7B). In contrast, at the same input doses, STAT5A/5B-deficient tester cells failed to give rise to significant numbers of cells of any lineage within peripheral blood, spleen, thymus, or bone marrow (Figures 6 and 7 and data not shown); in no case was the CD45.2+ signal greater than that of the background observed in animals not receiving tester cells. Complete competitive failure was also observed in 2 other independent experiments with highly backcrossed donors (G4 and G7, respectively).
Finally, because STAT5A/5B-deficient mice exhibited broad hematopoietic
deficiencies, we sought to identify the earliest stage of
differentiation at which defects were evident in the competitive repopulation assay. We failed to detect
lindimSca-1+ cells,
lindimSca-1neg/lo cells, or lin+
cells derived from STAT5A/5B-deficient cells at levels significantly above background (Figure 7C). Therefore, STAT5A/5B-deficient cells are
inferior to wild-type cells in their ability to occupy the limited
niche available for stem cells, early pluripotent cells, and
oligopotent progenitor cells. The STAT5A/5B
The transcription factor STAT5 is activated by multiple and diverse cytokines on binding to their cognate receptors, including several that act on the hematopoietic system. However, mice deficient for STAT5A, STAT5B, or both were reported to have surprisingly subtle deficiencies in hematolymphoid development, including reduction in peripheral T cells,13,14,18 impaired fetal erythropoiesis,20 and decreased survival of monocyte progenitors.21 Because numerous and complex regulatory pathways impinge on hematolymphoid development in vivo, we sought to define the hematologic features of STAT5A/5B-deficient mice to determine whether compensatory mechanisms may mask greater contributions of STAT5 in hematopoiesis in vivo. The first phase of our characterization revealed multilineage effects in peripheral blood at steady state, including marked decreases in erythrocytes and reduced numbers of circulating platelets. We also observed significant lymphopenia affecting both T cells and B cells. Moreover, although there was no abnormality in levels of peripheral blood neutrophils, a substantial decrease in the pool of mature neutrophils in the bone marrow was observed. In addition, histologic analysis of whole long bones and spleen in STAT5A/5B-deficient mice revealed extramedullary hematopoiesis in the enlarged spleens that was nearly exclusively erythropoietic tissue, as well as an exaggeration of myelopoiesis and few erythropoietic cells within intramedullary tissue in bone (data not shown). Hematologic stress in the mouse characteristically induces a myelopoietic dominance within bone marrow sites and heightened erythropoiesis within extramedullary sites such as the spleen.28 Therefore our histologic findings may represent further evidence of hematopoietic stress in these mice. We note that our peripheral blood analysis of STAT5A/5B-deficient mice differs from the initial characterization of these mice.18 One possible explanation is the age of the mice examined, because the influence of maturity has not been studied. Another possible factor is genetic background, because hematopoiesis is likely influenced by numerous strain-specific determinants. In any event, our findings indicate that there are defects in the circulating levels of 3 distinct blood lineages associated with signs of overall hematopoietic stress. Multilineage cytopenia can be caused by hyperactive consumptive
mechanisms broadly affecting peripheral blood cells, by multiple and
independent defects affecting production or survival of individual cell
types, or by a central bone marrow defect affecting progenitor cells
that are common to multiple lineages. The scope of the blood cell
abnormalities evident in STAT5A/5B To complement the flow cytometry data, we performed several in vivo reconstitution assays. The short-term radioprotection assay showed a severe defect in the ability of whole bone marrow from STAT5A/5B-deficient mice to protect a recipient from radiation-induced hematopoietic failure. In addition, we found that the reduction in the functional capability of the bone marrow from STAT5A/5B-deficient mice was not due to decreased homing ability. We used a second assay, the CFU-S assay, to quantitate early progenitor cells on the basis of functional criteria. These experiments revealed a dramatic reduction of hematopoietic colonies derived from STAT5A/5B-deficient animals. These results support our earlier finding that there is a diminution of the population (lindimSca-1neg/lo) within the bone marrow reported to contain oligopotent or lineage-committed cells and demonstrate that STAT5A/5B is a regulator of the biology of early progenitor cells. A decrease in the overall cell numbers in STAT5A/5B-deficient bone marrow could be caused by various mechanisms involving insensitivity of hematopoietic progenitors to one or more cytokines, including a reduction in survival half-life, a decrease in proliferation potential of progenitors, or an impaired execution of differentiation programs. We detected an increase in the rate of apoptosis in both the lin+ and lindimSca-1neg/lo fractions of bone marrow in STAT5A/5B-deficient mice. Although these studies do not elucidate the precise mechanism of antiapoptosis, impaired regulation of Bcl-X20,21 or other antiapoptotic mediators may be operative. We also detected an increased proportion of bone marrow cells in the S/G2/M phases of the cell cycle, a feature present in both the HSC and post-HSC populations. We propose that this increase in the proportion of cycling cells represents part of a compensation mechanism seeking to counter relative ineffective hematopoiesis in STAT5A/5B-deficient mice. Alternatively, slowed rates of progression through cell cycle in vivo might also underlie our results, as prolonged in vitro doubling times have been reported for STAT5A/5B-deficient progenitors.21 Finally, progenitors from STAT5A/5B-deficient mice have been shown to differentiate fully to mature cells in vitro,21 implying that there is no absolute loss of differentiation potential of progenitor cells in the absence of STAT5A/5B. Overall, these findings provide evidence of globally decreased cellular survival in bone marrow cells in the absence of STAT5A/5B, with a concurrent increase in the proportion of cycling cells among the least differentiated hematopoietic cells. To establish definitively the abnormalities in the stem cells of
STAT5A/5B-deficient mice, we applied the most rigorous functional assay
for stem cell fitness, the competitive repopulation
assay.26,27 Cells from STAT5A/5B Thus, these analyses of the role of STAT5 in hematopoiesis in vivo reveal that STAT5A/5B is an important positive factor that promotes HSC fitness and multilineage hematopoiesis. Relative insensitivity to cytokines such as G-CSF, TPO, growth hormone, IL-3, or others that act on progenitors could be responsible through either a reduction in the overall signal intensity or the loss of specific signals mediated by these cytokines. Bone marrow from STAT5A-deficient mice was shown to produce fewer in vitro colonies in the presence of flt3-ligand, a cytokine known to be important for hematopoietic progenitor homeostasis.29 At the cellular level, STAT5 may provide an antiapoptotic signal that lifts the threshold of survival in the context of internal and external apoptotic, antiapoptotic, proliferative, and differentiative signals. At the organismal level, this effect translates into lower viability of bone marrow hematopoietic cells, which likely results in fewer cells produced per stem cell that enter the differentiation program. In the context of lineage-specific defects shown in our analysis of post-HSC populations and in earlier reports regarding STAT5 deficiency, it remains unknown to what degree the cytopenias seen in these mice are attributable to the HSC, multilineage, or lineage-specific effects. In fact, evidence from some models in which stem cells or multilineage progenitors are affected30-32 suggests that defects at these stages alone may not induce mulitlineage cytopenias in some contexts. Nevertheless, our findings establish a novel and important role for STAT5 in the regulation of these early hematopoietic cells. This role is quantitative and nonessential, but genetic modifiers may control the degree of severity. These modifying loci could be responsible for multiple compensation mechanisms, such as extramedullary hematopoiesis and increases in bone marrow proliferation, which together allow the organism to achieve levels of hematopoietic production that are compatible with life but reduced nonetheless. Further studies in these animals may promote better understanding of the molecular pathogenesis of some forms of bone marrow failure. Additionally, STAT5 may act in a similar manner in human hematopoiesis and would thus be an attractive target for therapy in hematologic settings. Cytokine therapy is often used to ameliorate the phenotypes of lineage-specific and multilineage cytopenias, but it may be associated with increased rates of leukemic transformation in some settings.33 Perhaps directed activation of specific cytokine-mediated intracellular signals would serve to increase blood cell production without a concomitant rise in the rate of transformation.
We thank Dr James Ihle for kindly providing
STAT5A/5B
Submitted October 6, 2000; accepted August 23, 2001.
J.W.S. is supported by N.I.H. Immunology Training Grant AI07334 at the University of California, San Francisco. N.A. is supported by Damon-Runyon Fellowship 1548. B.H. is supported by P30 MH59037. This work was supported in part by N.I.H. grant GM54351 and the J. David Gladstone Institutes (M.A.G.).
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: Mark A. Goldsmith, Gladstone Institute of Virology and Immunology, PO Box 419100, San Francisco, CA 9414-9100; e-mail: mgoldsmith{at}gladstone.ucsf.edu.
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2000;96:429-436
© 2002 by The American Society of Hematology.
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  K. Ohmori, Y. Luo, Y. Jia, J. Nishida, Z. Wang, K. D. Bunting, D. Wang, and H. Huang IL-3 Induces Basophil Expansion In Vivo by Directing Granulocyte-Monocyte Progenitors to Differentiate into Basophil Lineage-Restricted Progenitors in the Bone Marrow and by Increasing the Number of Basophil/Mast Cell Progenitors in the Spleen J. Immunol., March 1, 2009; 182(5): 2835 - 2841. [Abstract] [Full Text] [PDF]
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 A. T. J. Wierenga, E. Vellenga, and J. J. Schuringa Maximal STAT5-Induced Proliferation and Self-Renewal at Intermediate STAT5 Activity Levels Mol. Cell. Biol., November 1, 2008; 28(21): 6668 - 6680. [Abstract] [Full Text] [PDF]
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 M. A. Kerenyi, F. Grebien, H. Gehart, M. Schifrer, M. Artaker, B. Kovacic, H. Beug, R. Moriggl, and E. W. Mullner Stat5 regulates cellular iron uptake of erythroid cells via IRP-2 and TfR-1 Blood, November 1, 2008; 112(9): 3878 - 3888. [Abstract] [Full Text] [PDF]
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 J. Iyer and N. C. Reich Constitutive nuclear import of latent and activated STAT5a by its coiled coil domain FASEB J, February 1, 2008; 22(2): 391 - 400. [Abstract] [Full Text] [PDF]
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H. Schepers, D. van Gosliga, A. T. J. Wierenga, B. J. L. Eggen, J. J. Schuringa, and E. Vellenga STAT5 is required for long-term maintenance of normal and leukemic human stem/progenitor cells Blood, October 15, 2007; 110(8): 2880 - 2888. [Abstract] [Full Text] [PDF]
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X. Dai, Y. Chen, L. Di, A. Podd, G. Li, K. D. Bunting, L. Hennighausen, R. Wen, and D. Wang Stat5 Is Essential for Early B Cell Development but Not for B Cell Maturation and Function J. Immunol., July 15, 2007; 179(2): 1068 - 1079. [Abstract] [Full Text] [PDF]
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 C.-H. Ting, C.-W. Lin, S.-L. Wen, H.-M. Hsieh-Li, and H. Li Stat5 constitutive activation rescues defects in spinal muscular atrophy Hum. Mol. Genet., March 1, 2007; 16(5): 499 - 514. [Abstract] [Full Text] [PDF]
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A. D. Panopoulos, L. Zhang, J. W. Snow, D. M. Jones, A. M. Smith, K. C. El Kasmi, F. Liu, M. A. Goldsmith, D. C. Link, P. J. Murray, et al. STAT3 governs distinct pathways in emergency granulopoiesis and mature neutrophils Blood, December 1, 2006; 108(12): 3682 - 3690. [Abstract] [Full Text] [PDF]
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M. Schmerer, I. Torregroza, A. Pascal, M. Umbhauer, and T. Evans STAT5 acts as a repressor to regulate early embryonic erythropoiesis Blood, November 1, 2006; 108(9): 2989 - 2997. [Abstract] [Full Text] [PDF]
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D. K. Taylor, P. T. Walsh, D. F. LaRosa, J. Zhang, M. A. Burchill, M. A. Farrar, and L. A. Turka Constitutive Activation of STAT5 Supersedes the Requirement for Cytokine and TCR Engagement of CD4+ T Cells in Steady-State Homeostasis J. Immunol., August 15, 2006; 177(4): 2216 - 2223. [Abstract] [Full Text] [PDF]
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A. Hoelbl, B. Kovacic, M. A. Kerenyi, O. Simma, W. Warsch, Y. Cui, H. Beug, L. Hennighausen, R. Moriggl, and V. Sexl Clarifying the role of Stat5 in lymphoid development and Abelson-induced transformation Blood, June 15, 2006; 107(12): 4898 - 4906. [Abstract] [Full Text] [PDF]
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A. T. J. Wierenga, H. Schepers, M. A. S. Moore, E. Vellenga, and J. J. Schuringa STAT5-induced self-renewal and impaired myelopoiesis of human hematopoietic stem/progenitor cells involves down-modulation of C/EBP{alpha} Blood, June 1, 2006; 107(11): 4326 - 4333. [Abstract] [Full Text] [PDF]
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 Y. Kato, A. Iwama, Y. Tadokoro, K. Shimoda, M. Minoguchi, S. Akira, M. Tanaka, A. Miyajima, T. Kitamura, and H. Nakauchi Selective activation of STAT5 unveils its role in stem cell self-renewal in normal and leukemic hematopoiesis J. Exp. Med., July 5, 2005; 202(1): 169 - 179. [Abstract] [Full Text] [PDF]
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C. Couldrey, H. L. Bradley, and K. D. Bunting A STAT5 modifier locus on murine chromosome 7 modulates engraftment of hematopoietic stem cells during steady-state hematopoiesis Blood, February 15, 2005; 105(4): 1476 - 1483. [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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R. van Os, L. M. Kamminga, and G. de Haan Stem Cell Assays: Something Old, Something New, Something Borrowed Stem Cells, December 1, 2004; 22(7): 1181 - 1190. [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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W. Tong and H. F. Lodish Lnk Inhibits Tpo-mpl Signaling and Tpo-mediated Megakaryocytopoiesis J. Exp. Med., September 7, 2004; 200(5): 569 - 580. [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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J. Kang, B. DiBenedetto, K. Narayan, H. Zhao, S. D. Der, and C. A. Chambers STAT5 Is Required for Thymopoiesis in a Development Stage-Specific Manner J. Immunol., August 15, 2004; 173(4): 2307 - 2314. [Abstract] [Full Text] [PDF]
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H. L. Bradley, C. Couldrey, and K. D. Bunting Hematopoietic-repopulating defects from STAT5-deficient bone marrow are not fully accounted for by loss of thrombopoietin responsiveness Blood, April 15, 2004; 103(8): 2965 - 2972. [Abstract] [Full Text] [PDF]
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S. Magne, S. Caron, M. Charon, M.-C. Rouyez, and I. Dusanter-Fourt STAT5 and Oct-1 Form a Stable Complex That Modulates Cyclin D1 Expression Mol. Cell. Biol., December 15, 2003; 23(24): 8934 - 8945. [Abstract] [Full Text] [PDF]
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M. A. Burchill, C. A. Goetz, M. Prlic, J. J. O'Neil, I. R. Harmon, S. J. Bensinger, L. A. Turka, P. Brennan, S. C. Jameson, and M. A. Farrar Distinct Effects of STAT5 Activation on CD4+ and CD8+ T Cell Homeostasis: Development of CD4+CD25+ Regulatory T Cells versus CD8+ Memory T Cells J. Immunol., December 1, 2003; 171(11): 5853 - 5864. [Abstract] [Full Text] [PDF]
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J. Zhang, M. Socolovsky, A. W. Gross, and H. F. Lodish Role of Ras signaling in erythroid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system Blood, December 1, 2003; 102(12): 3938 - 3946. [Abstract] [Full Text] [PDF]
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J. W. Snow, N. Abraham, M. C. Ma, B. G. Herndier, A. W. Pastuszak, and M. A. Goldsmith Loss of Tolerance and Autoimmunity Affecting Multiple Organs in STAT5A/5B-Deficient Mice J. Immunol., November 15, 2003; 171(10): 5042 - 5050. [Abstract] [Full Text] [PDF]
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C. P. Shelburne, M. E. McCoy, R. Piekorz, V. Sexl, K.-H. Roh, S. M. Jacobs-Helber, S. R. Gillespie, D. P. Bailey, P. Mirmonsef, M. N. Mann, et al. Stat5 expression is critical for mast cell development and survival Blood, August 15, 2003; 102(4): 1290 - 1297. [Abstract] [Full Text] [PDF]
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H. L. Bradley, T. S. Hawley, and K. D. Bunting Cell intrinsic defects in cytokine responsiveness of STAT5-deficient hematopoietic stem cells Blood, December 1, 2002; 100(12): 3983 - 3989. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
