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: 8789514
• 负责人: Jinsong Zhang
• 金额: $ 29.09万
• 依托单位: SAINT LOUIS UNIVERSITY
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789514
• 关键词: Aberrant; hematopoiesis; proteins; AML1; ETO

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.

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）]，其导致转录失调。这种易位通过将部分AML 1/RUNX 1转录因子连接到几乎完整的ETO蛋白（转录辅阻遏物家族的原型成员）而产生AML 1-ETO融合蛋白。该提案的长期目标是了解如何选择性地干扰AML 1-ETO活性，从而逆转白血病状态。本申请的直接目标是了解AML 1-ETO破坏正常转录程序的机制。AML 1-ETO的异常表达是t（8;21）AML的病理学原因。AML 1敲除和AML 1-ETO敲入小鼠模型之间的表型差异表明，AML 1-ETO除了使AML 1功能失调外还具有其他活性。虽然现在已经清楚AML 1-ETO干扰造血细胞自我更新、分化和凋亡中涉及的多种细胞事件，但仍不清楚AML 1-ETO如何去调节这些通路。最近，Zhang博士发现了AML 1-ETO与I类螺旋-环-螺旋转录因子（称为E蛋白）之间的分子相互作用。通过ETO结构域，AML 1-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。AML 1-ETO的致白血病潜力与其对与肿瘤抑制和细胞分化调节相关的E蛋白功能的抑制一致。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AML 1-ETO致白血病活性的ETO结构域相关;（ii）AML 1-ETO对E蛋白依赖性转录的抑制不仅涉及染色质依赖性抑制，还涉及对RNA聚合酶II转录复合物的直接抑制。这些发现导致了中心假设，即AML 1-ETO必须抑制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发生。本研究的主要目的是：（1）明确AML 1-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;和（目的2）为了确定E蛋白的失活对AML 1-ETO致白血病功能的贡献程度，并阐明t（8;21）白血病细胞中E蛋白相关的分子通路。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应该有助于识别新的治疗靶点和治疗AML的策略。

项目成果

Computational Modeling of Gene-Specific Transcriptional Repression, Activation and Chromatin Interactions in Leukemogenesis by LASSO-Regularized Logistic Regression.

• DOI: 10.1109/tcbb.2021.3078128
• 发表时间: 2021-11
• 期刊: IEEE/ACM transactions on computational biology and bioinformatics
• 作者: Steinauer N;Zhang K;Guo C;Zhang J
• 通讯作者: Zhang J

Nuclear receptor corepressor complexes in cancer: mechanism, function and regulation.

• 发表时间: 2014-10
• 期刊: American journal of clinical and experimental urology
• 影响因子: 1.2
• 作者: Madeline Wong;Chun Guo;Jinsong Zhang

Differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways.

• DOI: 10.1093/nar/gkt855
• 发表时间: 2014-01
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Gow CH;Guo C;Wang D;Hu Q;Zhang J
• 通讯作者: Zhang J

Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome.

• DOI: 10.1016/j.molmet.2017.05.001
• 发表时间: 2017-07
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Welch RD;Guo C;Sengupta M;Carpenter KJ;Stephens NA;Arnett SA;Meyers MJ;Sparks LM;Smith SR;Zhang J;Burris TP;Flaveny CA
• 通讯作者: Flaveny CA

Transcriptional and Genomic Control of Stem Cells in Development and Cancer.

发育和癌症中干细胞的转录和基因组控制。

• DOI: 10.1155/2017/2513598
• 发表时间: 2017
• 期刊: Stem cells international
• 影响因子: 4.3
• 作者: Zhang,Jinsong;Gow,Chien-Hung;Khan,Sohaib;Liu,Ying;Yang,Chuanwei
• 通讯作者: Yang,Chuanwei