biostudies-literatureUeda KNHLBI NIH HHSNCI NIH HHSNIHNIGMS NIH HHS529-547.e7https://www.ebi.ac.uk/biostudies/studies/S-EPMC8575661biostudies-literatureUnknown39(4)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 expressionCancer cellMDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism.PMC8575661R01 CA047296P30 CA013330F30 GM122308R01 HL139487T32 GM007288R01 CA217092R01 HL150832Narayanagari SRTaylor SJBoultwood JWheat JCBartholdy BChen JShan JCarvajal LASteidl UPradhan KXiong SPellagatti AGoto HUeda KVerma ALozano GSun DMontagna CKumari RSchwenger ETodorova TIBohorquez OSong YfalseMDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism.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 expression2021-01-01T00:00:00Z2021 Apr2026-05-09T03:09:39.912Z2025-02-18T23:32:13.641ZS-EPMC85756613366738410.1016/j.ccell.2021.02.006