A stalled chromatin regulatory network that mediates the oncogenic activity of Meningioma-1

介导 Meningioma-1 致癌活性的停滞染色质调控网络

基本信息

批准号：
10445974
负责人：
KATHRIN M BERNT
金额：
$ 35.05万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445974
关键词：
ATP phosphohydrolase Acute Myelocytic Leukemia Affect Behavior Binding Binding Sites Bone Marrow Bone Marrow Cells Bromodomain CRISPR/Cas technology Catalytic Domain Cell Line Cessation of life ChIP-seq Chromatin Complex Consensus Sequence Development Diagnosis Drug Targeting Enhancers Excision Exposure to Gene Expression Regulation Genes Genetic Transcription Goals Hematopoietic Hematopoietic stem cells Human In Vitro Individual Kinetics Knowledge Malignant Neoplasms Mediating Meningioma by Site Meningioma-1 Methods Molecular Mus Mutation Myelogenous Nucleosomes Oncogenic Patients Play Positioning Attribute Process Prognosis Regulation Reporting Role Sampling Site Specificity System Transcription Coactivator Variant acute myeloid leukemia cell drug development gain of function genome editing in vivo inhibitor insight leukemia leukemic transformation leukemogenesis loss of function member molecular imaging mutant novel overexpression patient population prevent progenitor programs promoter recruit single molecule stem targeted treatment transcription factor

项目摘要

PROJECT SUMMARY High expression of the transcriptional co-activator Meningioma-1 (MN1) is common in AML, and associated with a poor prognosis. Forced expression of MN1 in murine hematopoietic progenitors induces an aggressive leukemia. We recently discovered that the primary interaction partner of MN1 is the BAF nucleosome- positioning complex. MN1 stabilizes BAF on chromatin. MN1 binding is associated with sustained active enhancer chromatin at enhancers regulating a hematopoietic stem/progenitor program. We hypothesize that MN1 stabilizes promoter-enhancer contacts at these sites through a BAF dependent mechanism. The goal of this project is to uncover the molecular mechanism of MN1-mediated leukemic transformation. A better understanding of how MN1 causes leukemia may identify opportunities for targeted therapies in a patient population who is failing conventional AML therapy.

项目摘要转录共激活剂脑膜瘤1（MN1）的高表达在AML中很常见，并且相关预后不良。 MN1在鼠造血祖细胞中的强迫表达会诱导侵略性白血病。我们最近发现，MN1的主要相互作用伙伴是BAF核小体 - 定位复合物。 MN1在染色质上稳定BAF。 MN1结合与持续活跃有关增强剂染色质在调节造血茎/祖细胞计划的增强剂方面。我们假设这一点 MN1通过BAF依赖机制稳定这些位点的启动子增强剂的触点。目标该项目的是揭示MN1介导的白血病转化的分子机制。更好了解MN1如何导致白血病可以确定患者靶向疗法的机会常规AML治疗失败的人群。