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

Mol Cell. 2021 Jun 3;81(11):2332-2348.e9. doi: 10.1016/j.molcel.2021.04.014. Epub 2021 May 10.

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.

Keywords: AML; BAF; IDP; IDR; Meningioma-1; SWI/SNF; intrinsically disordered protein/region; leukemia; polyQ.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromatin / pathology
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism
  • Enhancer Elements, Genetic
  • Female
  • Gene Expression Regulation, Leukemic
  • Gene Regulatory Networks
  • Humans
  • Intrinsically Disordered Proteins / genetics*
  • Intrinsically Disordered Proteins / metabolism
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Peptides / genetics
  • Peptides / metabolism
  • Protein Interaction Mapping
  • Protein Stability
  • Protein Transport
  • Signal Transduction
  • Survival Analysis
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Chromatin
  • Intrinsically Disordered Proteins
  • MN1 protein, human
  • Mn1 protein, mouse
  • Nuclear Proteins
  • Peptides
  • Trans-Activators
  • Transcription Factors
  • Tumor Suppressor Proteins
  • polyglutamine
  • SMARCA4 protein, human
  • Smarca4 protein, mouse
  • DNA Helicases