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.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Bishop, Terry Rogers
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Schools of Medicine
United States
Zip Code
Fernando, Josephine; Faber, Travis W; Pullen, Nicholas A et al. (2013) Genotype-dependent effects of TGF-*1 on mast cell function: targeting the Stat5 pathway. J Immunol 191:4505-13
Pullen, Nicholas A; Barnstein, Brian O; Falanga, Yves T et al. (2012) Novel mechanism for Fc{epsilon}RI-mediated signal transducer and activator of transcription 5 (STAT5) tyrosine phosphorylation and the selective influence of STAT5B over mast cell cytokine production. J Biol Chem 287:2045-54
Du, Jinwei; Chen, Yu; Li, Qiang et al. (2012) HIF-1? deletion partially rescues defects of hematopoietic stem cell quiescence caused by Cited2 deficiency. Blood 119:2789-98
Vaughan, Tamisha Y; Verma, Sheetal; Bunting, Kevin D (2011) Grb2-associated binding (Gab) proteins in hematopoietic and immune cell biology. Am J Blood Res 1:130-134
Liu, Zhuoming; Yang, Amy; Wang, Zhengqi et al. (2011) Multiple apoptotic defects in hematopoietic cells from mice lacking lipocalin 24p3. J Biol Chem 286:20606-14
Xiong, Yin; Li, Zejuan; Ji, Min et al. (2011) MIR29B regulates expression of MLLT11 (AF1Q), an MLL fusion partner, and low MIR29B expression associates with adverse cytogenetics and poor overall survival in AML. Br J Haematol 153:753-7
Li, Geqiang; Wang, Zhengqi; Miskimen, Kristy L et al. (2010) Gab2 promotes hematopoietic stem cell maintenance and self-renewal synergistically with STAT5. PLoS One 5:e9152
Li, G; Miskimen, K L; Wang, Z et al. (2010) Effective targeting of STAT5-mediated survival in myeloproliferative neoplasms using ABT-737 combined with rapamycin. Leukemia 24:1397-405
Li, Geqiang; Miskimen, Kristy L; Wang, Zhengqi et al. (2010) STAT5 requires the N-domain for suppression of miR15/16, induction of bcl-2, and survival signaling in myeloproliferative disease. Blood 115:1416-24
Wang, Zhengqi; Li, Geqiang; Tse, William et al. (2009) Conditional deletion of STAT5 in adult mouse hematopoietic stem cells causes loss of quiescence and permits efficient nonablative stem cell replacement. Blood 113:4856-65

Showing the most recent 10 out of 24 publications