Publication — IRIC

Intrinsically disordered Meningioma-1 stabilizes the BAF complex to cause AML.

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.

Date de publication
3 June 2021
Chercheurs
Riedel SS, Lu C, Xie HM, Nestler K, Vermunt MW, Lenard A, Bennett L, Speck NA, Hanamura I, Lessard J, Blobel GA, Garcia BA, Bernt KM
Référence PubMed
Mol Cell 2021;81(11):2332-2348.e9
ID PubMed
33974912
Affiliation
Division of Pediatric Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.