MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism

Cancer Cell. 2021 Apr 12;39(4):529-547.e7. doi: 10.1016/j.ccell.2021.02.006. Epub 2021 Mar 4.

Abstract

MDMX is overexpressed in the vast majority of patients with acute myeloid leukemia (AML). We report that MDMX overexpression increases preleukemic stem cell (pre-LSC) number and competitive advantage. Utilizing five newly generated murine models, we found that MDMX overexpression triggers progression of multiple chronic/asymptomatic preleukemic conditions to overt AML. Transcriptomic and proteomic studies revealed that MDMX overexpression exerts this function, unexpectedly, through activation of Wnt/β-Catenin signaling in pre-LSCs. Mechanistically, MDMX binds CK1α and leads to accumulation of β-Catenin in a p53-independent manner. Wnt/β-Catenin inhibitors reverse MDMX-induced pre-LSC properties, and synergize with MDMX-p53 inhibitors. Wnt/β-Catenin signaling correlates with MDMX expression in patients with preleukemic myelodysplastic syndromes and is associated with increased risk of progression to AML. Our work identifies MDMX overexpression as a pervasive preleukemic-to-AML transition mechanism in different genetically driven disease subtypes, and reveals Wnt/β-Catenin as a non-canonical MDMX-driven pathway with therapeutic potential for progression prevention and cancer interception.

Keywords: CK1α; MDMX; acute myeloid leukemia; cancer interception; myelodysplastic syndromes; precision prevention; preleukemia; preleukemic stem cells; targeted therapy; β-Catenin.

Publication types

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

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Mice
  • Myelodysplastic Syndromes / drug therapy
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / metabolism
  • Proteomics / methods
  • Proto-Oncogene Proteins / metabolism*
  • Wnt Signaling Pathway / genetics
  • Wnt Signaling Pathway / physiology
  • beta Catenin / metabolism*

Substances

  • CTNNB1 protein, human
  • Cell Cycle Proteins
  • MDM4 protein, human
  • Mdm4 protein, mouse
  • Proto-Oncogene Proteins
  • beta Catenin