The role of Hhex in normal and malignant lymphopoiesis

Hhex 在正常和恶性淋巴细胞生成中的作用

基本信息

批准号：
8786284
负责人：
Charnise Goodings
金额：
$ 1.67万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8786284
关键词：
Acute Lymphocytic Leukemia Acute T Cell Leukemia Adolescent and Young Adult Age B-Cell Development B-Lymphocytes Binding Biological Assay Blood Cells Bone Marrow Bone Marrow Transplantation Candidate Disease Gene Cell Count Cell Lineage Cells Cessation of life Child Complement DNA Binding Data Defect Development Embryo Employee Strikes Gene Expression Regulation Genes Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Homeobox Homeobox Genes Homeodomain Proteins Human In Vitro Knock-out Lymphoid Lymphoma Lymphopoiesis Maintenance Malignant - descriptor Malignant Neoplasms Methods Modeling Molecular Mus Myelogenous Myeloid Leukemia Myeloid Progenitor Cells N-terminal Oncogenes Organ Pathway interactions Phenotype Proline-Rich Domain Proteins Repressor Proteins Research Retroviridae Rhombotin 2 Role Stem cells Stress T-Cell Development T-Lymphocyte Testing Transgenes United States chromatin immunoprecipitation embryonic stem cell gene repression homeodomain irradiation leukemia malformation mutant progenitor public health relevance self-renewal stem transcription factor

项目摘要

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.

描述（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，仍有很多工作要做，因为它在 20 岁以下的儿童、青少年和年轻人中造成的死亡人数比任何其他癌症都要多。当造血功能出现缺陷时，就会发生白血病。。造血功能常常因干细胞和祖细胞中异常表达的转录因子而失调。其中一种转录因子已被鉴定为造血表达同源盒 (Hhex) 基因，存在于干细胞、骨髓和 B 细胞祖细胞中。 Hhex 失调与 T 细胞、B 细胞和骨髓性白血病的发展有关。 Hhex 强制表达会在 T-ALL 发生之前诱导 T 细胞祖细胞的分化阻断并增加自我更新。了解Hhex在造血中的正常功能；我们使用 vav-Cre 转基因诱导了 floxed Hhex 的条件敲除。我们发现在稳定状态下，大多数细胞计数正常，但 B 细胞存在显着缺陷发育类似于在由 Hhex-/- ES 细胞制成的嵌合小鼠中观察到的情况。令人惊讶的是，我们还发现在应激条件下，Hhex cKO 小鼠也表现出 T 细胞发育缺陷。我们假设 Hhex 调节对正常淋巴发育重要的基因，并且这些基因的调节需要 Hhex 的转录功能。为了检验这一假设，我们提出两个目标（1）研究 Hhex 功能的分子决定因素（2）以确定 Hhex 在淋巴发育中的转录靶点。这些研究将增强我们对Hhex在淋巴发育中作用的理解，也将为我们提供Hhex的潜在靶点，从而为潜在的白血病治疗方法提供新的靶点。