IDP mediated transcriptional stabilization as a cause of AML

项目摘要 内在无序蛋白脑膜瘤-1（MN 1）的高表达在AML中很常见， 并伴有预后不良。MN 1在小鼠造血细胞中的强制表达 祖细胞会诱发侵袭性白血病我们最近发现， MN 1的伴侣是BAF核小体定位复合物。MN 1稳定染色质上的BAF。 MN 1结合与持续的活性增强子染色质在增强子调节细胞凋亡相关。 造血干/祖细胞计划。有趣的是，MN 1的整个编码框架是无序的。我们 假设MN 1通过增加多- 价，低亲和力的相互作用，导致高浓度的BAF和早期 造血转录因子更好地了解MN 1如何导致白血病可能 确定常规AML失败患者人群中靶向治疗的机会 疗法

PROJECT SUMMARY High expression of the intrinsically disordered protein 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. Intriguingly, MN1’s entire coding frame is disordered. We hypothesize that MN1 causes AML by overstabilizing transcriptional hubs by increasing multi- valent, low affinity interactions that result in high local concentrations of BAF and early hematopoietic transcription factors. A better understanding of how MN1 causes leukemia may identify opportunities for targeted therapies in a patient population who is failing conventional AML therapy.