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

Koki Ueda, Rajni Kumari, Emily Schwenger, Justin C. Wheat, Oliver Bohorquez, Swathi Rao Narayanagari, Samuel J. Taylor, Luis A. Carvajal, Kith Pradhan, Boris Bartholdy, Tihomira I. Todorova, Hiroki Goto, Daqian Sun, Jiahao Chen, Jidong Shan, Yinghui Song, Cristina Montagna, Shunbin Xiong, Guillermina Lozano, Andrea PellagattiJacqueline Boultwood, Amit Verma, Ulrich Steidl

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)529-547.e7
JournalCancer Cell
Volume39
Issue number4
DOIs
StatePublished - Apr 12 2021

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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