Abstract
The p53 inhibitor MDMX is overexpressed in the vast majority of patients with AML; however, a causative role of MDMX in leukemogenesis has not yet been investigated. Mdmx transgenic mice (Mdmx-Tg) displayed increased number, proliferation and competitive advantage of hematopoietic stem cells compared to WT littermates. Crossing Mdmx-Tg with preleukemic mouse models representing frequent alterations in human AML, we generated three distinct compound models. We found that Mdmx overexpression triggered progression of each of the different chronic/asymptomatic preleukemic conditions to overt AML, and thereby markedly shortened survival. RNA sequencing revealed that Mdmx overexpression exerted this function through activation of Wnt/b-Catenin signaling in pre-LSC. Mechanistically, we found that MDMX bound CK1a, a canonical degrader of b-Catenin, and led to accumulation and nuclear translocation of b-Catenin. WNT/b-Catenin inhibitors or exogenous overexpression of CK1a were both effective in reversing Mdmx-induced pre-LSC properties, and showed further synergism in combination with MDMX inhibitor treatment. Competitive advantage and accumulation of b-Catenin upon Mdmx overexpression were still seen upon crossing into a p53-/- background, demonstrating that Mdmx-driven WNT/b-Catenin activation and its functional consequences are, at least part, independent of p53. Lastly, upregulation of WNT/b-Catenin pathways correlated with MDMX overexpression in large cohorts of patients with MDS and was associated with increased risk of progression to AML and poor survival. Our work identifies MDMX overexpression as a pervasive preleukemic-to-AML switch mechanism effective in different genetically-driven disease subtypes, and reveals WNT/b-Catenin as a novel, non-canonical p53-independent MDMX-driven pathway with therapeutic potential for progression prevention and cancer interception.
Published Version
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