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stem cell function stem cell survival tool transcription factor transcriptome tumor tumorigenesis ubiquitin ligase unpublished works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器与一般转录机械进行通信，并因此，确保将生物学输入转化为特定的基因表达程序。调解人复合物是这样的共激活因子，在增强剂和启动子的RNA聚合酶II（POL II）。它是一个大型大分子复合物，进一步排列在四个模块中会议高灵活性：头部，中间，尾巴和激酶模块。激酶的成员在固体（子宫内膜，肺，颈椎，结肠癌）和血液（DLBCL，CLL，ALL，AML）癌症。但是， MED12突变及其在疾病开始和进展中的作用仍然难以捉摸。我们最近专注于关于造血干细胞（HSC）分化的激酶模块的功能和Med12的功能和转型。我们发现MED12蛋白表达在后泛素后在后翻译中控制连接酶FBXW7，一种经常突变的肿瘤抑制剂。我们还发现Med12是 HSC功能，如Med12的体内缺失，损害了HSC的存活，并导致小鼠致死性。一起使用必需的造血转录因子，MED12共占HSC特异性增强子。 Med12 耗尽破坏了p300结合，从而导致快速增强子“灭活”和钥匙表达的丧失 HSC特异性基因。这些数据表明Med12的表达和功能可以由于多个而改变机制，包括针对基因本身或其调节剂的体细胞突变（FBXW7），这是异常功能会导致恶性转化。该建议旨在阐明分子放松调节增强剂活性的关键调节剂（例如Med12）时，机制发生了变化。虽然有被认为是Med12突变会议是“功能获得的”，没有机械研究执行最新。为了解决这个关键问题，我们正在研究慢性淋巴细胞性白血病（CLL），西方世界中最常见的成年白血病。剖析调解人功能的破坏如何贡献对于这种异质且复杂的疾病，我们使用：a）转录/表观遗传学的组合携带Med12突变的人类患者样品的表征，b）CRISPR修饰并针对ES 转基因小鼠模型研究Med12病变启动和维持疾病的能力，以及，C）带有MED12的CRISPR修饰细胞系中的体外转录组，表观遗传学和3D染色体拓扑突变。定义调解器和增强子调节导致恶性肿瘤的机制转化将有助于开发针对血液恶性肿瘤和固体的新型疗法肿瘤。靶向介体药物的小分子最近鉴定出这种鉴定疗法可以触及。

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.