The zinc-finger transcriptional repressor Gfi-1 has a critical intrinsic role in maintaining the function of hematopoietic stem cells (HSCs) and also controls a variety of their progeny at distinct, later stages of hematopoietic differentiation. HSCs lacking Gfi-1 display severely reduced activity in transplantation assays and cannot compete with wildtype HSCs in the bone marrow. In the absence of Gfi-1, HSCs exhibit strikingly increased proliferation rates and are found more frequently in active phases of the cell cycle. This suggests that Gfi-1 functions to restrict proliferation in HSCs and contrasts findings in T-lymphocytes in which it promotes proliferation. The molecular basis of Gfi-1's action at precise stages of hematopoietic differentiation is unknown, as are the molecular mechanisms modulating its function, depending on the cellular context. Clarification of the detailed mechanisms of Gfi-1 in HSCs is pivotal for developing strategies to exploit its biology in order to manipulate stem cells. The highly complex hematopoietic phenotype that follows disruption of Gfi-1 in mice is a major obstacle in our complete understanding HSCs and their more mature descendants. We have engineered a novel, conditional mouse strain that permits temporally controlled and lineage specific disruption of Gfi-1 that will enable us to dissect the roles Gfi-1 in adult HSCs and subsequently, in specific lineages.
The specific aims of this proposal are: 1) to characterize the impact of induced disruption of Gfi-1 in HSCs of adult mice, 2) to identify and validate the target genes of Gfi-1 in HSCs, and 3) to elucidate the role of Gfi-1 in B-cells. Relevance to public health: Deciphering the molecular regulation of adult hematopoietic stem cells is critical for the development of urgently needed strategies to maintain, expand, and manipulate stem cells. Furthermore, it may serve as paradigm for the biology of stem cells in other tissues, leukemia, and cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Hematopoiesis Study Section (HP)
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Howcroft, Thomas K
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Massachusetts General Hospital
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Foudi, Adlen; Kramer, Daniel J; Qin, Jinzhong et al. (2014) Distinct, strict requirements for Gfi-1b in adult bone marrow red cell and platelet generation. J Exp Med 211:909-27
Shi, Lewis Zhichang; Kalupahana, Nishan S; Turnis, Meghan E et al. (2013) Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derived regulatory T cells. Proc Natl Acad Sci U S A 110:E3198-205
Hock, Hanno (2010) Some hematopoietic stem cells are more equal than others. J Exp Med 207:1127-30
Foudi, Adlen; Hochedlinger, Konrad; Van Buren, Denille et al. (2009) Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nat Biotechnol 27:84-90