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

• 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
• 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

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（由申请人提供）：据估计，在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，但仍有更多的工作可以成功治疗这种白血病，因为它比儿童，青少年和20岁以下的年轻人中的任何其他癌症都要多。当造血功能有缺陷时，就会发生白血病。造血通常被干细胞和祖细胞中异常表达的转录因子失调。这些转录因子之一已被鉴定为造血表达的同源盒（Hhex）基因，其存在于干细胞、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。在T-ALL发作之前，Hhex强制表达诱导T细胞祖细胞的分化阻滞和增加的自我更新。为了了解Hhex在造血中的正常功能，我们使用vav-Cre转基因诱导了floxed Hhex的条件性敲除。我们发现，在稳态时，大多数细胞计数是正常的，但有一个明显的缺陷，在B细胞 发育类似于在由Hhex-/- ES细胞制成的嵌合小鼠中观察到的发育。令人惊讶的是，我们还发现，在应激条件下，Hhex cKO小鼠也显示出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。为了验证这一假设，我们提出了两个目标（1）调查Hhex功能的分子决定因素（2）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在淋巴发育中的作用的理解，也将为我们提供Hhex的潜在靶点，这将为潜在的白血病治疗方法提供新的靶点。