Date of Award

12-2009

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Molecular Therapeutics and Cell Signaling

Research Advisor

Brian P. Sorrentino, M.D.

Committee

Paul A. Ney, M.D. Guillermo Oliver, Ph.D. Edward Park, Ph.D. Lawrence Pfeffer, Ph.D.

Keywords

hematopoietic progenitor cells, Hemgn, HOXB4, self-renewal

Abstract

Overexpression of HOXB4, a member of Homeobox transcription factor family, promotes expansion of hematopoietic stem and progenitor cells bothin vivo and in vitro. However, the molecular mechanisms underlying this effect are not well understood. In order to identify direct target genes of HOXB4 in primary murine hematopoietice progenitor cells, we induced HOXB4 function in lineage-negative, murine bone marrow cells, using a tamoxifen-inducibleHOXB4-ERT2fusion protein. Seventy seven genes with differentially changed expression in early response to HOXB4 have been identified as candidate target genes. Among them, we show that Hemogen (Hemgn), encoding a nuclear protein specifically expressed in hematopoietic stem and progenitor cells, is a direct transcriptional target of HOXB4, and that HOXB4 binds to the promoter region of Hemgn. More importantly, when overexpressed in bone marrowcells, Hemgn promotes expansion of 5-fluorouracil (5-FU) treated bone marrow cells in both liquid and semi-solid cultures, recapitulating the effects of HOXB4. Furthermore, both Hemgn and HOXB4 can protect bone marrow cells from apoptosis. Our results identify an important direct transcriptional target of HOXB4 that can confer expansion of primitive myeloid progenitor cells.

DOI

10.21007/etd.cghs.2009.0154

Comments

One year embargo expired December 2010

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