Aberrant hematopoiesis: E proteins and AML1-ETO in leukemogenesis

异常造血：E 蛋白和 AML1-ETO 在白血病发生中的作用

• 批准号: 7730246
• 负责人: Jinsong Zhang
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7730246
• 关键词: AML1-ETO fusion protein; Acute Myelocytic Leukemia; American; Apoptosis; Binding; Blood Cells; British; Cell Differentiation process; Cells; Chromatin; Chromosome abnormality; Complex; Differentiation and Growth; E protein; Event; Family; Genetic Transcription; Goals; Helix-Turn-Helix Motifs; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Knock-in Mouse; Knock-out; Lead; Learning; Leukemic Cell; Leukocytes; Malignant Neoplasms; Mediating; Molecular; Pathway interactions; Patients; Proteins; RNA Polymerase II; RUNX1 gene; Regulation; Repression; Testing; Transcription Repressor/Corepressor; Tumor Suppression; Tumor Suppressor Proteins; base; human CBFA2T1 protein; leukemia; leukemogenesis; member; mouse model; new therapeutic target; programs; protein function; public health relevance; self-renewal; t(8; 21)(q22; q22); transcription factor; treatment strategy

DESCRIPTION (provided by applicant): The most frequent cause of acute myeloid leukemia (AML) is the 8;21 translocation [t(8;21)], which results in transcriptional dysregulation. This translocation generates an AML1-ETO fusion protein by joining part of the AML1/RUNX1 transcription factor to a nearly complete ETO protein, the prototypical member of a family of transcriptional corepressors. The long-term goal of this proposal is to learn how to selectively interfere with AML1-ETO activity, and thereby reverse the leukemogenic state. The immediate goal of this application is to understand the mechanisms by which AML1-ETO disrupts the normal transcriptional program. Aberrant expression of AML1-ETO is the pathological cause of t(8;21) AML. Phenotypic differences between the AML1 knockout and the AML1-ETO knock-in mouse models indicate that AML1-ETO has other activities besides deregulation of AML1 functions. Although it is now clear that AML1-ETO interferes with multiple cellular events involved in hematopoietic cell self-renewal, differentiation, and apoptosis, it remains unclear how AML1-ETO deregulates these pathways. Recently, Dr. Zhang discovered a molecular interaction between AML1-ETO and the class I helix-loop-helix transcriptional factors known as E proteins. Through the ETO domain, AML1-ETO aberrantly represses E protein-mediated transcription. E proteins have tumor- suppressor activities that are frequently inactivated in cancers. That is, they promote apoptosis and control hematopoietic cell differentiation. The leukemogenic potential of AML1-ETO is consistent with its inhibition of E protein functions related to both tumor suppression and regulation of cell differentiation. Dr. Zhang's preliminary studies show (i) that the ETO domains involved in repressing E protein- dependent transcription correlate with those involved in the leukemogenic activities of AML1-ETO; and (ii) that repression of E protein-dependent transcription by AML1-ETO involves not only chromatin-dependent inhibition, but also direct inhibition of the RNA polymerase II transcription complex. These findings led to the central hypothesis that AML1-ETO must repress both the chromatin-dependent and chromatin- independent transcription mediated by E proteins to allow for leukemogenesis. The hypothesis will be tested through the following two aims: (Aim 1) To define the mechanisms by which AML1-ETO represses E protein-dependent transcription at the level of chromatin as well as at the level of basal transcription machinery; and (Aim 2) To determine the extent to which inactivation of E proteins contributes to AML1-ETO leukemogenic function, and to elucidate the molecular pathways associated with E proteins in t(8;21) leukemic cells. A better understanding of the molecular mechanisms underlying t(8;21) AML, and the aberrant functions of proteins involved in leukemogenesis should lead to the identification of new therapeutic targets and strategies for treatment of AML. PUBLIC HEALTH RELEVANCE: Leukemia is a cancer of the blood that involves abnormal growth and differentiation of certain types of white blood cells. In some cases, leukemia is caused by a chromosomal abnormality that leads to inactivation of E protein, a cellular protein that normally controls blood cell differentiation and proliferation. This project will define the mechanism of E protein inactivation, which could lead to new treatments for leukemia based on the reactivation of this protein to reverse the leukemic condition.

描述（由申请人提供）：急性髓性白血病（AML）最常见的原因是8；21易位[t(8;21)]，导致转录失调。这种易位通过将AML1/RUNX1转录因子的一部分连接到一个几乎完整的ETO蛋白上而产生AML1-ETO融合蛋白，ETO蛋白是一个转录辅抑制子家族的典型成员。这项建议的长期目标是学习如何选择性地干扰AML1-ETO活性，从而逆转白血病发生状态。本应用程序的直接目标是了解AML1-ETO破坏正常转录程序的机制。AML1-ETO的异常表达是t(8;21) AML的病理原因。AML1敲除和AML1- eto敲除小鼠模型之间的表型差异表明，AML1- eto除解除AML1功能外还有其他活性。虽然现在已经清楚AML1-ETO干扰造血细胞自我更新、分化和凋亡的多个细胞事件，但AML1-ETO如何解除这些通路的调控尚不清楚。最近，张博士发现AML1-ETO与I类螺旋-环-螺旋转录因子（即E蛋白）之间存在分子相互作用。通过ETO结构域，AML1-ETO异常抑制E蛋白介导的转录。E蛋白具有肿瘤抑制活性，但在癌症中经常失活。也就是说，它们促进细胞凋亡并控制造血细胞分化。AML1-ETO的白血病潜能与其抑制与肿瘤抑制和细胞分化调节相关的E蛋白功能是一致的。Zhang博士的初步研究表明(i)参与抑制E蛋白依赖性转录的ETO结构域与参与AML1-ETO白血病活性的结构域相关；（ii） AML1-ETO对E蛋白依赖性转录的抑制不仅包括染色质依赖性抑制，还包括RNA聚合酶ii转录复合物的直接抑制。这些发现导致了一个中心假设，即AML1-ETO必须抑制由E蛋白介导的染色质依赖性和染色质非依赖性转录，以允许白血病的发生。该假设将通过以下两个目标进行验证：（目标1）确定AML1-ETO在染色质水平和基础转录机制水平上抑制E蛋白依赖性转录的机制；（目的2）确定E蛋白失活对AML1-ETO白血病功能的贡献程度，并阐明t（8;21）白血病细胞中与E蛋白相关的分子途径。更好地了解t(8;21) AML的分子机制，以及参与白血病发生的蛋白质的异常功能，将有助于确定AML的新治疗靶点和治疗策略。公共卫生相关性：白血病是一种血液癌症，涉及某些类型白细胞的异常生长和分化。在某些情况下，白血病是由染色体异常导致E蛋白失活引起的，E蛋白是一种通常控制血细胞分化和增殖的细胞蛋白。该项目将确定E蛋白失活的机制，这可能会导致基于该蛋白的再激活来逆转白血病的新治疗方法。