It has been estimated that in the year 2013, 23,720 people in the United States will die from leukemia. Despite many breakthroughs in leukemia research there is still more that can be done to successfully treat this leukemia because it is responsible for more deaths than any other cancer among children, adolescents and young adults under age 20. Leukemia occurs when there is a defect in hematopoiesis. Hematopoiesis is often deregulated by transcription factors that are aberrantly expressed in stem and progenitor cells. One of these transcription factors has been identified as Hematopoietically-expressed Homeobox (Hhex) gene that is present in stem cells, myeloid, and B-cell progenitors. Hhex deregulation is implicated in the development of T-cell, B-cell and myeloid leukemia. Hhex enforced expression induces a differentiation block and increased self-renewal of T-cell progenitor cells prior to the onset of T-ALL. To understand Hhex's normal function in hematopoiesis;we induced a conditional knockout of floxed Hhex using the vav-Cre transgene. We found that at steady state, most cell counts are normal but there is a striking defect in B-cell development similar to what was observed in chimeric mice made from Hhex-/- ES cells. Surprisingly, we also found that under stressed conditions, Hhex cKO mice also show a defect in T-cell development. We hypothesize that Hhex regulates genes important for normal lymphoid development and that the regulation of these genes requires the transcriptional function of Hhex. To test this hypothesis we propose two aims (1) to investigate the molecular determinants for Hhex function (2) to identify the transcriptional targets of Hhex in lymphoid development. These studies will enhance our understanding of the role of Hhex in lymphoid development and will also provide us with potential targets of Hhex which will provide new targets for potential leukemia treatment methods.
The hematopoietically expressed homeobox (Hhex) protein is important for normal B-cell development and has been found to be activated along with Lmo2 in T-cell acute lymphoblastic leukemia (T-ALL). However, the mechanism by which Hhex operates in normal and malignant hematopoiesis is not well understood. My proposal seeks to understand the roles of Hhex in both normal and malignant hematopoiesis.
|Goodings, Charnise; Smith, Elizabeth; Mathias, Elizabeth et al. (2015) Hhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation. Stem Cells 33:2628-41|