MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism
Menée notamment à l'aide de 5 modèles murins de leucémie, cette étude met en évidence le rôle de la protéine MDMX dans la progression d'un état pré-leucémique vers une leucémie myéloïde aiguë
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/?-Catenin signaling in pre-LSCs. Mechanistically, MDMX binds CK1α and leads to accumulation of ?-Catenin in a p53-independent manner. Wnt/?-Catenin inhibitors reverse MDMX-induced pre-LSC properties, and synergize with MDMX-p53 inhibitors. Wnt/?-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/?-Catenin as a non-canonical MDMX-driven pathway with therapeutic potential for progression prevention and cancer interception.
Cancer Cell 2021