The role of Hhex in normal and malignant lymphopoiesis

描述（由申请人提供）：据估计，2013年美国将有23,720人死于白血病。尽管白血病研究取得了许多突破，但要成功治疗这种白血病还有很多工作要做，因为在儿童、青少年和20岁以下的年轻人中，这种白血病造成的死亡人数比其他任何癌症都要多。当造血功能有缺陷时，就会发生白血病。造血功能经常被干细胞和祖细胞中异常表达的转录因子调控。其中一种转录因子已被确定为造血表达同源盒（Hhex）基因，存在于干细胞、髓细胞和b细胞祖细胞中。Hhex的失调与t细胞、b细胞和髓性白血病的发生有关。在T-ALL发病前，Hhex的强制表达诱导t细胞祖细胞分化阻滞和自我更新增加。了解Hhex在造血中的正常功能；我们使用vav-Cre转基因诱导了有条件的敲除Hhex。我们发现，在稳定状态下，大多数细胞计数正常，但b细胞有明显的缺陷

DESCRIPTION (provided by applicant): 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.