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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK059380-12
Application #
8634762
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Bishop, Terry Rogers
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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:
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; Medrzycki, Magdalena; Bunting, Silvia T et al. (2015) Stat5-deficient hematopoiesis is permissive for Myc-induced B-cell leukemogenesis. Oncotarget 6:28961-72
Liu, Xia; Zheng, Hong; Yu, Wen-Mei et al. (2015) Maintenance of mouse hematopoietic stem cells ex vivo by reprogramming cellular metabolism. Blood 125:1562-5
Sabnis, Himalee; Bradley, Heath L; Bunting, Silvia T et al. (2014) Capillary nano-immunoassay for Akt 1/2/3 and 4EBP1 phosphorylation in acute myeloid leukemia. J Transl Med 12:166
Chatterjee, Anindya; Ghosh, Joydeep; Ramdas, Baskar et al. (2014) Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis. Cell Rep 9:1333-48
Qing, Yulan; Wang, Zhengqi; Bunting, Kevin D et al. (2014) Bcl2 overexpression rescues the hematopoietic stem cell defects in Ku70-deficient mice by restoration of quiescence. Blood 123:1002-11
Wang, Zhengqi; Li, Geqiang; Bunting, Kevin D (2014) STAT5 N-domain deleted isoforms are naturally occurring hypomorphs partially rescued in hematopoiesis by transgenic Bcl-2 expression. Am J Blood Res 4:20-6
Wang, Zhengqi; Bunting, Kevin D (2013) STAT5 in hematopoietic stem cell biology and transplantation. JAKSTAT 2:e27159
Wang, Chenhui; Wu, Ling; Bulek, Katarzyna et al. (2013) The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90. Nat Immunol 14:72-81

Showing the most recent 10 out of 45 publications