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

Résumé en anglais

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.