The transcription factors STAT5A/B regulate GM-CSF–mediated granulopoiesis

Kimura, Akiko; Rieger, Michael A.; Simone, James; Chen, Weiping; Wickre, Mark C.; Zhu, Bing-Mei; Hoppe, Philipp S.; O’Shea, John J.; Schroeder, Timm; Hennighausen, Lothar

doi:10.1182/blood-2009-04-216390

Cited by 63 publications

(55 citation statements)

References 48 publications

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“…Initially, in STAT5 Ϫ/Ϫ animals no defects were observed in myelopoiesis, suggesting that STAT5 is dispensable for myeloid development, 10 although later it was shown that granulopoiesis under myelosuppressive conditions was impaired. 45 Further studies are required to elucidate why constitutive activation of STAT5 appears insufficient to alter phenotypes in GMPs under steady-state conditions. Furthermore, it is noteworthy that whereas STAT5 activation efficiently induced erythroid commitment from HSC, CMP, and MEP compartments, which is in agreement with previously published data, 17,25,46 no erythroid differentiation could be induced by STAT5 in GMPs.…”

Section: Discussionmentioning

confidence: 99%

Identification of HIF2α as an important STAT5 target gene in human hematopoietic stem cells

Fátrai

Wierenga

Daenen

et al. 2011

Blood

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The transcription factor signal transducer and activator of transcription 5 (STAT5) fulfills essential roles in selfrenewal in mouse and human hematopoietic stem cells (HSCs), and its persistent activation contributes to leukemic transformation, although little molecular insight into the underlying mechanisms has been obtained. In the present study, we show that STAT5 can impose longterm expansion exclusively on human HSCs, not on progenitors. This was asso-

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Section: Discussionmentioning

confidence: 99%

Identification of HIF2α as an important STAT5 target gene in human hematopoietic stem cells

Fátrai

Wierenga

Daenen

et al. 2011

Blood

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“…Although the potential of LT-HSCs to form colonies was unchanged by GADD45G, their ability to form secondary colonies after replating was severely decreased, indicating that GADD45G accelerates their differentiation ( Figure 1G). To assess the differentiation kinetics of LT-HSCs into GMPs induced by GADD45G at the single-cell level, we continuously observed individual LT-HSCs and their progeny by time-lapse microscopy and cell tracking, a technology that records individual cell behavior in ontogeny pedigrees (Kimura et al, 2009;). LT-HSCs were transduced with lentiviruses coding for GADD45G or a control and were immediately administered to time-lapse microscopy ( Figure 1H).…”

Section: Gadd45g Is Activated By Cytokines and Immediatelymentioning

confidence: 99%

Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells

Thalheimer

Wingert

Giacomo

et al. 2014

Experimental Hematology

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SUMMARYThe balance of self-renewal and differentiation in long-term repopulating hematopoietic stem cells (LT-HSC) must be strictly controlled to maintain blood homeostasis and to prevent leukemogenesis. Hematopoietic cytokines can induce differentiation in LT-HSCs; however, the molecular mechanism orchestrating this delicate balance requires further elucidation. We identified the tumor suppressor GADD45G as an instructor of LT-HSC differentiation under the control of differentiation-promoting cytokine receptor signaling. GADD45G immediately induces and accelerates differentiation in LT-HSCs and overrides the self-renewal program by specifically activating MAP3K4-mediated MAPK p38. Conversely, the absence of GADD45G enhances the self-renewal potential of LT-HSCs. Videomicroscopy-based tracking of single LT-HSCs revealed that, once GADD45G is expressed, the development of LT-HSCs into lineage-committed progeny occurred within 36 hr and uncovered a selective lineage choice with a severe reduction in megakaryocytic-erythroid cells. Here, we report an unrecognized role of GADD45G as a central molecular linker of extrinsic cytokine differentiation and lineage choice control in hematopoiesis.

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“…38,[40][41][42] Although initially all of these factors were believed to act on committee myeloid lineages, intracellular flow cytometry data from several groups using HSC/HPC fractions shows marked STAT5 activation. 38,43,44 In HSCs, Mpl synergizes with early acting cytokines [45][46][47][48] and regulates multilineage progenitors and HSC self-renewal.…”

Section: Stat5 Activation In Hematopoietic Stem and Progenitor Cellsmentioning

confidence: 99%

“…6 However, STAT5 is required at later stages for normal granulopoiesis. 42 Therefore, STAT5 acts at many levels of hematopoiesis and the overall output in the peripheral blood lineages is a composite of the effects on HSC, primitive HPC, and the lineage committed progenitors. EPO is also a major activator of STAT5 in the erythroid lineage [61][62][63] and it can synergize with SCF to activate STAT5, 64 whereas activation of STAT5 by SCF alone in HSC/ HPC still remains unclear.…”

Section: Stat5 Activation In Hematopoietic Stem and Progenitor Cellsmentioning

confidence: 99%

STAT5 in hematopoietic stem cell biology and transplantation

Wang

Bunting

2013

JAK-STAT

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Hematopoiesis is a finely tuned process with intricate feedback mechanisms for regulating production of mature blood cells. Many of the lineage commitment and differentiation decisions of hematopoietic cells are dictated by the delicate balance of transcription factors. Most basal transcription factors are constitutively active, but some require activation in order to translocate to the nucleus and regulate gene expression. JAK-STAT pathway activation provides a rapid way for extracellular signals to rapidly transduce signals resulting in STAT activation within minutes and gene expression within hours of the initial cytokine exposure. Once tyrosine phosphorylated, transcriptionally activated STATs accumulate in the nucleus.Signal transducer and activator of transcription-5 (STAT5) comprises two separate genes, 1 STAT5A and STAT5B, which collectively are major regulators of normal hematopoiesis with pleiotropic roles in hematopoietic stem cell (HSC), [1][2][3][4][5][6][7] hematopoietic progenitor cell (HPC), [8][9][10] and mature cell populations.11-14 Although the differences in phenotype of mice lacking STAT5A vs. STAT5B 15,16 were primarily assumed to be due to differences in tissue specific gene expression, functional differences have been more recently discovered. For example, ERβ regulation appears to be mediated only by STAT5B,17 and STAT5B-deficient patients have been discovered that have reduced numbers of regulatory T cells and short stature. [18][19][20] These phenotypes are consistent with major non-redundant roles for STAT5B in regulation of target genes such as FoxP3 and IGF1. Knockdown studies of STAT5A and STAT5B in human CD4 + T cells confirmed this specificity for FoxP3 21 and knockdown studies in IL-3 stimulated murine BaF3 cells identified overlapping and unique sets of STAT5 target genes by chromatin immunoprecipitation. 22Interestingly, the ability for STAT5 binding to modulate gene expression appears to be under additional levels of regulation such as serine phosphorylation [23][24][25] and glycosylation 26 which may influence interactions with CREB-binding protein. Serine phosphorylation has been described for most STATs 27,28 although the positive or negative influence of this modification has been debated. 29 The normal role of STAT5 serine phosphorylation in hematopoiesis has not been tested and the effect may be very cell type and cell context specific. Serine phosphorylation could facilitate interaction of STAT5 with critical accessory proteins required for nuclear localization of tyrosine phosphorylated STAT5. Cooperative signals mediated by serine and tyrosine phosphorylation could also be lineage-specific and further studies of serine phosphorylation deficient STAT5 mutants are needed to fully understand this level of regulation in HSC and throughout hematopoiesis.We have reported that STAT5 is required for HSC "fitness" with its deficiency resulting in greatly impaired long-term multilineage competitive repopulation capacity of fetal liver 4,10 and bone marrow 2-7 HSC in lethall...

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The transcription factors STAT5A/B regulate GM-CSF–mediated granulopoiesis

Cited by 63 publications

References 48 publications

Identification of HIF2α as an important STAT5 target gene in human hematopoietic stem cells

Identification of HIF2α as an important STAT5 target gene in human hematopoietic stem cells

Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells

STAT5 in hematopoietic stem cell biology and transplantation

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