STAT5 in hematopoietic stem cell biology and transplantation

Abstract

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...

Transcriptional and epigenetic networks of helper T and innate lymphoid cells

“…Deletion of both alleles typically results in growth retardation and perinatal lethality due to anemia . STAT5 is a critical factor for the hematopoietic system and the entire lymphoid compartment, controlling HSC fitness, lymphoid cell development/homeostasis and, later on, Th polarization . Its relevance relates to the importance of c‐kit (stem cell factor) and IL‐7 signaling for HSC and lymphoid development, and IL‐15 signaling for generation of conventional NK cells and homeostasis of memory T cells .…”

“…cell development/homeostasis and, later on, Th polarization (195)(196)(197). Its relevance relates to the importance of c-kit (stem cell factor) and IL-7 signaling for HSC and lymphoid development, and IL-15 signaling for generation of conventional NK cells and homeostasis of memory T cells (198,199).…”

Identification of STAT3 and STAT5 proteins in the rat suprachiasmatic nucleus and the Day/Night difference in astrocytic STAT3 phosphorylation in response to lipopolysaccharide

“…Jak2/STAT3 signaling has also been implicated in NMDA‐induced long‐term depression in the hippocampus (Nicolas et al, ). STAT5 was originally discovered as a transcription factor mediating the prolactin response in mammary epithelial cells and has been studied extensively to determine its role in growth hormone signaling, leukemogenesis, and proliferation of various cancer cells (Watson and Burdon, ; Bennett et al, ; Wang and Bunting, ). Data also indicate the involvement of STATs in neuronal and glial differentiation.…”

GRAM domain-containing protein 1A (GRAMD1A) promotes the expansion of hepatocellular carcinoma stem cell and hepatocellular carcinoma growth through STAT5

“…For example, STAT5 promotes the proliferation, survival and self-renewal of hematopoietic stem cell2324. STAT5 increases the AR stability, promotes castration-resistant prostate cancer growth, tumor metastasis and the self-renewal of prostate cancer stem cells252627.…”