Transcriptional regulation of TAL1/SCL in normal and malignant hematopoiesis

描述(申请人提供)：TAL1/SCL基因的异常激活与大多数T细胞急性淋巴细胞白血病(T-ALL)有关。作为一种造血特异的碱性螺旋-环-螺旋转录因子，TAL1在正常造血过程中对造血干细胞的更新和谱系发育是必不可少的。鉴于其与正常造血和T-ALL的相关性，了解该转录因子的转录调控将有助于阐明控制正常造血和白血病发生的分子机制。许多证据表明，TAL1与转录共激活因子和共抑制因子有关，这对TAL1‘S在红系分化中的功能有不同的影响。因此，我们假设组蛋白修饰酶在造血过程中调节TAL1介导的转录调控，它们的错误调节可能有助于T细胞白血病的发展。在这一应用中，我们重点研究了相反的组蛋白修饰酶是如何调节TAL1在造血和白血病发生中的功能的。本研究的具体目的是：1)阐明组蛋白去甲基酶在TAL1介导的转录和造血调控中的生物学功能；2)分析组蛋白甲基转移酶在TAL1介导的红系分化过程中转录调控中的作用；3)了解组蛋白修饰酶在TAL1诱导的正常造血和白血病发生中的分子基础。通过完成这项拟议的研究，我们希望进一步了解TAL1指导的转录活性如何有助于正常造血和白血病转化。我们还将了解TAL1相关的组蛋白修饰酶在这些过程中的作用。这些信息最终将有助于设计新的治疗方法来治疗白血病。此外，这项研究还将阐明转录因子对造血干细胞生长和分化的控制。项目简介：转录因子TAL1/SCL对正常血细胞的形成至关重要，并经常与一种特殊形式的白血病有关，T细胞急性淋巴细胞白血病(T-ALL)是一种恶性疾病，几乎没有有效的治疗方法。在这项提案中，我们将探索TAL1如何调节血细胞的形成和白血病的发展。这些研究将为TAL1在调节血细胞发育中的作用提供新的见解，并将有助于设计新的治疗白血病的方法。

DESCRIPTION (provided by applicant): Aberrant activation of the TAL1/SCL gene has been involved in majority of T cell acute lymphoblastic leukemia (T-ALL). As a hematopoietic-specific basic helix-loop-helix transcription factor, TAL1 is essential for hematopoietic stem cell renewal and lineage development during normal hematopoiesis. Given its relevance to normal hematopoiesis and T-ALL, understanding the transcriptional control of this transcription factor will elucidate the molecular mechanisms underlying the control of normal hematopoiesis and leukemogenesis. Several lines of evidence have established that TAL1 associates with transcriptional coactivators and corepressors which differentially affect TAL1's function in erythroid differentiation. Hence, we hypothesize that histone modifying enzymes regulate TAL1-mediated transcriptional control during hematopoiesis and their misregulations would contribute to the development of T-cell leukemia. In this application, we focus on investigating how the opposite histone modifying enzymes that we have identified as TAL1-associated cofactors regulate TAL1 function in hematopoiesis and leukemogenesis. The specific aims of this research proposal are: 1) Elucidate the biological function of histone demethylase in the control of TAL1-mediated transcription and hematopoiesis; 2) Analyze the role of histone methyltransferase in TAL1-mediated transcriptional regulation during erythroid differentiation; 3) Understand the molecular basis of histone modifying enzymes in TAL1-induced normal hematopoiesis and leukemogenesis. By completing the proposed research, we expect to further understand how TAL1- directed transcriptional activity contributes to normal hematopoiesis and leukemic transformation. We will also gain knowledge on the role of TAL1-associated histone modifying enzymes in these processes. This information will eventually help to design new therapeutic approaches to treat leukemia. Moreover, the study will shed light on the control of transcription factors on hematopoietic stem cell growth and differentiation. Project Narative: Transcription factor TAL1/SCL is critical for the formation of normal blood cells and is frequently associated with a specific form of leukemia, T cell acute lymphoblastic leukemia (T-ALL) which is a malignant disease with very few effective treatments. In this proposal, we will explore how TAL1 regulates the formation of blood cells and the development of leukemia. These studies will provide novel insights into TAL1 function in the regulation of blood cell development and will help to design new therapeutic approaches to treat leukemia.