Division of Pediatric Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Biochemistry and Biophysics, University of Pennsylvania, and the Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Mol Cell. 2021 Jun 3;81(11):2332-2348.e9. doi: 10.1016/j.molcel.2021.04.014. Epub 2021 May 10.
Meningioma-1 (MN1) overexpression in AML is associated with poor prognosis, and forced expression of MN1 induces leukemia in mice. We sought to determine how MN1 causes AML. We found that overexpression of MN1 can be induced by translocations that result in hijacking of a downstream enhancer. Structure predictions revealed that the entire MN1 coding frame is disordered. We identified the myeloid progenitor-specific BAF complex as the key interaction partner of MN1. MN1 over-stabilizes BAF on enhancer chromatin, a function directly linked to the presence of a long polyQ-stretch within MN1. BAF over-stabilization at binding sites of transcription factors regulating a hematopoietic stem/progenitor program prevents the developmentally appropriate decommissioning of these enhancers and results in impaired myeloid differentiation and leukemia. Beyond AML, our data detail how the overexpression of a polyQ protein, in the absence of any coding sequence mutation, can be sufficient to cause malignant transformation.
脑膜瘤 1 型（MN1）在 AML 中的过表达与预后不良相关，并且 MN1 的强制表达可在小鼠中诱导白血病。我们试图确定 MN1 如何导致 AML。我们发现，MN1 的过表达可由导致下游增强子劫持的易位诱导。结构预测表明，整个 MN1 编码框是无序的。我们确定髓系祖细胞特异性 BAF 复合物是 MN1 的关键相互作用伙伴。MN1 过度稳定增强子染色质上的 BAF，该功能与 MN1 内长聚谷氨酰胺延伸直接相关。在调节造血干细胞/祖细胞程序的转录因子的结合位点上 BAF 的过度稳定会阻止这些增强子的发育适当退役，导致髓系分化受损和白血病。除 AML 之外，我们的数据详细说明了在没有任何编码序列突变的情况下，聚 Q 蛋白的过表达如何足以导致恶性转化。
