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.
Congratulations to Professor Ulrich Steidl and co-authors from Albert Einstein College of Medicine, The University of Texas MD Anderson Cancer Center (USA), and University of Oxford (UK) for their excellent work published in Cancer Cell (IF=50)!
InvivoChem is proud to provide Professor Ulrich Steidl’s team with our high-quality product LGK974 (WNT974) (Cat #: V1353; CAS #: 1243244-14-5, PORCN (Porcupine) inhibitor) for this research.
References: Cancer Cell. 2021 Apr 12;39(4):529-547.e7. doi: 10.1016/j.ccell.2021.02.006.