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

• 批准号: 10579293
• 负责人: KATHRIN M BERNT
• 金额: $ 42.97万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 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/10579293
• 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; leukemia treatment; 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

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 转录共激活因子脑膜瘤-1（MN 1）的高表达在AML中很常见， 预后很差MN 1在小鼠造血祖细胞中的强制表达诱导了侵袭性的 白血病我们最近发现MN 1的主要相互作用伙伴是BAF核小体- 定位复杂。MN 1稳定染色质上的BAF。MN 1结合与持续的活性相关 在调节造血干/祖细胞程序的增强子处的增强子染色质。我们假设 MN 1通过BAF依赖性机制稳定这些位点的启动子-增强子接触。目标 本项目的主要目的是揭示MN 1介导白血病转化的分子机制。更好的 了解MN 1如何导致白血病可能会发现患者靶向治疗的机会 常规AML治疗失败的人群。