Mechanisms of enhancer regulation in leukemia

白血病增强子调控机制

基本信息

  • 批准号:
    10321638
  • 负责人:
  • 金额:
    $ 49.24万
  • 依托单位:
  • 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

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.
摘要

项目成果

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Iannis Aifantis其他文献

Iannis Aifantis的其他文献

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{{ truncateString('Iannis Aifantis', 18)}}的其他基金

The role of inflammation in the regulation of immune response in acute myeloid leukemia
炎症在急性髓系白血病免疫反应调节中的作用
  • 批准号:
    10729281
  • 财政年份:
    2023
  • 资助金额:
    $ 49.24万
  • 项目类别:
Dissecting innate immune signaling in pre-leukemia evolution
剖析白血病前期进化中的先天免疫信号
  • 批准号:
    10584536
  • 财政年份:
    2022
  • 资助金额:
    $ 49.24万
  • 项目类别:
Dissecting innate immune signaling in pre-leukemia evolution
剖析白血病前期进化中的先天免疫信号
  • 批准号:
    10462192
  • 财政年份:
    2022
  • 资助金额:
    $ 49.24万
  • 项目类别:
mRNA stability and its impact on hematopoiesis and acute leukemia
mRNA稳定性及其对造血和急性白血病的影响
  • 批准号:
    10339742
  • 财政年份:
    2022
  • 资助金额:
    $ 49.24万
  • 项目类别:
mRNA stability and its impact on hematopoiesis and acute leukemia
mRNA稳定性及其对造血和急性白血病的影响
  • 批准号:
    10543125
  • 财政年份:
    2022
  • 资助金额:
    $ 49.24万
  • 项目类别:
Regulation of emergency hematopoiesis by the ubiquitin-proteasome system
泛素-蛋白酶体系统对紧急造血的调节
  • 批准号:
    10279596
  • 财政年份:
    2021
  • 资助金额:
    $ 49.24万
  • 项目类别:
Regulation of emergency hematopoiesis by the ubiquitin-proteasome system
泛素-蛋白酶体系统对紧急造血的调节
  • 批准号:
    10634676
  • 财政年份:
    2021
  • 资助金额:
    $ 49.24万
  • 项目类别:
Mechanisms of enhancer regulation in leukemia
白血病增强子调控机制
  • 批准号:
    10545714
  • 财政年份:
    2019
  • 资助金额:
    $ 49.24万
  • 项目类别:
Project 3: Oncogenic triggers and their influence on 3D chromosomal architecture
项目 3:致癌触发因素及其对 3D 染色体结构的影响
  • 批准号:
    10652283
  • 财政年份:
    2019
  • 资助金额:
    $ 49.24万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    10434092
  • 财政年份:
    2019
  • 资助金额:
    $ 49.24万
  • 项目类别:

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