Intrinsically Disordered Meningioma-1 Stabilizes the BAF Complex to Cause AML

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2021 May 11

PMID 33974912

Citations 19

Authors

Simone S Riedel

Congcong Lu

Hongbo M Xie

Kevin Nestler

Marit W Vermunt

Alexandra Lenard

Laura Bennett

Nancy A Speck

Ichiro Hanamura

Julie A Lessard

Gerd A Blobel

Benjamin A Garcia

Kathrin M Bernt

Affiliations

Soon will be listed here.

Abstract

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.

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