Our lab has been studying the role of signal transducer and activator of transcription 5 (STAT5) in hematopoiesis for more than a decade and we have identified important roles in hematopoietic and immune cell biology. Despite these advances in understanding the severity and broad range of defects in mice lacking STAT5, the mechanisms by which STAT5-mediated transcriptional activation controls hematopoiesis are not fully defined. We recently reported that although STAT5 drives multilineage differentiation it plays a surprising role in promoting hematopoietic stem cell quiescence. We have already identified key target genes involved in this process, including tie2 and p57. There are big differences between the hematopoietic stem cell and progenitor niches in regard to their oxidation potential and STAT5 is sensitive to reactive oxygen and nitrogen species. We will explore the overall hypothesis that STAT5-mediated transcriptional activation in the hypoxic hematopoietic stem cell niche is unique from that in the oxidation promoting hematopoietic progenitor niche and that changes in STAT5 function depend on the microenvironment and can control engraftment, mobilization, lineage differentiation, and quiescence. We have already performed preliminary gene expression array analysis of STAT5-deficient c-Kit+Sca-1+Lin- (KLS) cells and have utilized chromatin immunoprecipitation assays that identified bcl2 as a novel STAT5 direct target gene. Therefore we will test the following aims: 1) We will use a novel viable hematopoietic-specific conditional knockout mouse to study how STAT5 modulates juvenile seeding of the niches, migration, and mobilization. 2) We have demonstrated that the long-term repopulating hematopoietic stem cell pool is uniquely sensitive to STAT5 deletion, whereas the short-term repopulating pool is spared. We will analyze lineage differentiation in STAT5-deficient mice and characterize lymphoid priming and predisposition to B-lineage acute lymphoblastic leukemia. 3) We will perform STAT5 ChIP-qPCR experiments in multipotent hematopoietic cells and identify mechanisms of redox regulation. Collectively, these three aims will provide important insight into the functional and molecular regulation of hematopoiesis by STAT5 in response to early acting cytokines and may lead to improved therapeutic approaches for treating blood disorders.
Signal transducer and activator of transcription 5 (STAT5) activation is critical for engraftment of transplanted blood-forming hematopoietic stem cells. The aim of this proposal is to understand how STAT5 promotes movement into and out of specialized bone marrow niches and reciprocally how different niche environments influence STAT5 function. This understanding will help broaden therapeutic applications of hematopoietic stem cell transplantation.
|Lee, Jocelyn A; Wang, Zhengqi; Sambo, Danielle et al. (2018) Global loss of leucine carboxyl methyltransferase-1 causes severe defects in fetal liver hematopoiesis. J Biol Chem 293:9636-9650|
|Wang, Zhengqi; Bunting, Kevin D (2017) Stat5 deficiency decreases transcriptional heterogeneity and supports emergence of hematopoietic sub-populations. Oncotarget 8:22477-22482|
|Bourgeais, Jerome; Ishac, Nicole; Medrzycki, Magdalena et al. (2017) Oncogenic STAT5 signaling promotes oxidative stress in chronic myeloid leukemia cells by repressing antioxidant defenses. Oncotarget 8:41876-41889|
|Liu, W; Yu, W-M; Zhang, J et al. (2017) Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations. Leukemia 31:1415-1422|
|Metts, Jonathan; Bradley, Heath L; Wang, Zhengqi et al. (2017) Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells. Sci Rep 7:4447|
|Park, Jino; Kim, Soojin; Joh, Joongho et al. (2016) MLLT11/AF1q boosts oncogenic STAT3 activity through Src-PDGFR tyrosine kinase signaling. Oncotarget 7:43960-43973|
|Sabnis, Himalee S; Bradley, Heath L; Tripathi, Shweta et al. (2016) Synergistic cell death in FLT3-ITD positive acute myeloid leukemia by combined treatment with metformin and 6-benzylthioinosine. Leuk Res 50:132-140|
|Wang, Zhengqi; Bunting, Kevin D (2016) STAT5 activation in B-cell acute lymphoblastic leukemia: damned if you do, damned if you don't. Cancer Cell Microenviron 3:|
|Wang, Zhengqi; Medrzycki, Magdalena; Bunting, Silvia T et al. (2015) Stat5-deficient hematopoiesis is permissive for Myc-induced B-cell leukemogenesis. Oncotarget 6:28961-72|
|Wu, Ling; Zepp, Jarod A; Qian, Wen et al. (2015) A novel IL-25 signaling pathway through STAT5. J Immunol 194:4528-34|
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