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

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。

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.