Mechanisms of enhancer regulation in leukemia

白血病增强子调控机制

基本信息

批准号：
10545714
负责人：
Iannis Aifantis
金额：
$ 49.24万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10545714
关键词：
3-Dimensional Address Adult Animal Model Architecture B-Lymphocytes Binding Biological Biology Blood Cell Line Cell Lineage Cell model Cells Cervical Chromosomes Chronic Lymphocytic Leukemia Clustered Regularly Interspaced Short Palindromic Repeats Colon Carcinoma Communication Complex Data Development Disease EP300 gene Endometrial Enhancers Ensure Epigenetic Process FBXW7 gene Gene Expression Generations Genes Genetic Genetic Transcription Genomics Growth Head Hematopoietic Hematopoietic Neoplasms Hematopoietic stem cells Human In Vitro Laboratories Lead Lesion Lung Macromolecular Complexes Malignant - descriptor Malignant Neoplasms Maps Mature B-Lymphocyte Mediating Mediator Molecular Mus Mutagenesis Mutate Mutation Patients Phosphotransferases Proteins Publishing RNA Polymerase II Recurrence Regulation Role Sampling Scientist Solid Solid Neoplasm Somatic Mutation Specialist Study models Tail Techniques Testing Transgenic Mice Translating Tumor Suppressor Proteins Western World adult leukemia cell transformation chromosome conformation capture chronic lymphocytic leukemia cell flexibility gain of function genomic locus hematopoietic stem cell differentiation in vivo insight large cell Diffuse non-Hodgkin&apos s lymphoma leukemia member microdeletion mouse model multidisciplinary mutant new therapeutic target novel pharmacologic pre-clinical programs promoter protein expression recruit small molecule stem cell function stem cell survival tool transcription factor transcriptome tumor tumorigenesis ubiquitin ligase unpublished works

项目摘要

ABSTRACT Transcription factors require coactivators to communicate with the general transcription machinery and, thereby, ensure that biological inputs are translated into specific gene-expression programs. The Mediator complex is such a coactivator and acts as a ‘molecular bridge’ between transcription factor at enhancers and RNA polymerase II (Pol II) at promoters. It is a large macromolecular complex further arranged in four modules that confer high flexibility: the head, the middle, the tail and the kinase module. The member of the kinase module Mediator 12 (MED12) has been found frequently mutated in both solid (endometrial, lung, cervical, colon carcinomas) and blood (DLBCL, CLL, ALL, AML) cancers. However, the underlying mechanisms of MED12 mutations and its role in disease initiation and progression remain elusive. We have recently focused on the function of the kinase module and specifically MED12 in hematopoietic stem cell (HSC) differentiation and transformation. We found that MED12 protein expression is controlled post-translationally by the ubiquitin ligase FBXW7, a frequently mutated tumor suppressor. We also found that MED12 is an essential regulator of HSC function, as in vivo deletion of MED12 compromises HSC survival and leads to mouse lethality. Together with essential hematopoietic transcription factors, MED12 co-occupies HSC-specific enhancers. MED12 depletion destabilizes P300 binding thus leading to rapid enhancer “inactivation”, and loss of expression of key HSC-specific genes. These data suggest that MED12 expression and function can be altered due to multiple mechanisms, including somatic mutations targeting the gene itself or its regulators (FBXW7), and that this aberrant function can lead to malignant transformation. This proposal aims to shed light on the molecular mechanisms altered upon deregulation of a crucial regulator of enhancer activity, such as MED12. While it has been suggested that MED12 mutations confer a “gain-of-function”, no mechanistic studies have been performed up to date. To address this key question, we are studying chronic lymphocytic leukemia (CLL), the most common adult leukemia in the western world. To dissect how disruption of Mediator function contributes to this heterogeneous and complex disease, we use a combination of: a) transcriptional/epigenetic characterization of human patient samples harboring MED12 mutations, b) CRISPR-modified and ES targeted transgenic mouse models to investigate the ability of MED12 lesions to initiate and maintain disease, and, c) in vitro transcriptome, epigenetic and 3D-chromosome topology in CRISPR-modified cell lines with MED12 mutations. Defining the mechanisms by which Mediator and enhancer regulation contribute to malignant transformation will be beneficial for the development of novel therapies targeting blood malignancies and solid tumors. The recent identification of small molecules targeting Mediator pharmacologically suggests that such therapies are within reach.

抽象的转录因子需要共激活剂与一般转录机制进行通信，并且，从而确保生物输入转化为特定的基因表达程序。复合物就是这样一种共激活剂，充当增强子和转录因子之间的“分子桥梁” 启动子处的 RNA 聚合酶 II (Pol II) 它是进一步排列为四个模块的大分子复合物。赋予高度灵活性：头部、中部、尾部和激酶模块。模块介体 12 (MED12) 在实体（子宫内膜、肺、宫颈、结肠癌）和血液（DLBCL、CLL、ALL、AML）癌症，但其潜在机制。 MED12 突变及其在疾病发生和进展中的作用仍然难以捉摸。激酶模块（特别是 MED12）在造血干细胞 (HSC) 分化中的功能我们发现 MED12 蛋白的表达受到泛素的翻译后控制。连接酶 FBXW7，一种经常突变的肿瘤抑制因子，我们还发现 MED12 是一个重要的调节因子。 HSC 功能，因为体内 MED12 缺失会损害 HSC 存活并导致小鼠死亡。 MED12 与必需的造血转录因子共同占据 HSC 特异性增强子。耗尽会破坏 P300 结合的稳定性，从而导致增强子快速“失活”，并导致关键蛋白表达丧失这些数据表明 MED12 的表达和功能可能因多种因素而改变。机制，包括针对基因本身或其调节因子（FBXW7）的体细胞突变，并且这该提议旨在阐明分子功能异常可能导致恶性转化。增强子活性的关键调节因子（例如 MED12）放松管制后，机制会发生变化。有人认为 MED12 突变会带来“功能获得”，但尚未进行任何机制研究为了解决这个关键问题，我们正在研究慢性淋巴细胞白血病（CLL）。西方世界最常见的成人白血病剖析调解功能的破坏如何造成的。对于这种异质且复杂的疾病，我们结合使用：a) 转录/表观遗传携带 MED12 突变的人类患者样本的特征，b) CRISPR 修饰和 ES 靶向转基因小鼠模型，用于研究 MED12 损伤引发和维持疾病的能力，以及 c) 使用 MED12 在 CRISPR 修饰的细胞系中进行体外转录组、表观遗传和 3D 染色体拓扑定义介体和增强子调节导致恶性的机制。转化将有利于针对血液恶性肿瘤和实体瘤的新疗法的开发最近对介导物的药理学小分子的鉴定表明，这种作用。治疗是触手可及的。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Author Correction: An inflammatory state remodels the immune microenvironment and improves risk stratification in acute myeloid leukemia.

作者更正：炎症状态重塑免疫微环境并改善急性髓系白血病的风险分层。

DOI：
10.1038/s43018-023-00518-x
发表时间：
2023
期刊：
Nature cancer
影响因子：
22.7
作者：
Lasry,Audrey;Nadorp,Bettina;Fornerod,Maarten;Nicolet,Deedra;Wu,Huiyun;Walker,ChristopherJ;Sun,Zhengxi;Witkowski,MatthewT;Tikhonova,AnastasiaN;Guillamot-Ruano,Maria;Cayanan,Geraldine;Yeaton,Anna;Robbins,Gabriel;Obeng,EstherA;
通讯作者：

Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors.

DOI：
10.1056/nejmoa2114110
发表时间：
2022-02-24
期刊：
The New England journal of medicine
影响因子：
0
作者：
通讯作者：

Cell-by-Cell Deconstruction of Stem Cell Niches.

DOI：
10.1016/j.stem.2020.06.013
发表时间：
2020-07-02
期刊：
Cell stem cell
影响因子：
23.9
作者：
Tikhonova AN;Lasry A;Austin R;Aifantis I
通讯作者：
Aifantis I

SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2.

DOI：
10.1016/j.immuni.2021.05.006
发表时间：
2021-06-08
期刊：
Immunity
影响因子：
32.4
作者：
Lu Q;Liu J;Zhao S;Gomez Castro MF;Laurent-Rolle M;Dong J;Ran X;Damani-Yokota P;Tang H;Karakousi T;Son J;Kaczmarek ME;Zhang Z;Yeung ST;McCune BT;Chen RE;Tang F;Ren X;Chen X;Hsu JCC;Teplova M;Huang B;Deng H;Long Z;Mudianto T;Jin S;Lin P;Du J;Zang R;Su TT;Herrera A;Zhou M;Yan R;Cui J;Zhu J;Zhou Q;Wang T;Ma J;Koralov SB;Zhang Z;Aifantis I;Segal LN;Diamond MS;Khanna KM;Stapleford KA;Cresswell P;Liu Y;Ding S;Xie Q;Wang J
通讯作者：
Wang J

Computational model of CAR T-cell immunotherapy dissects and predicts leukemia patient responses at remission, resistance, and relapse.