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MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism

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MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism

Cancer Cell

Fecha de publicación: 12 de abril de 2021

Autores: Koki Ueda, Rajni Kumari, Emily Schwenger, Justin C.Wheat, Oliver Bohorquez, Swathi-Rao Narayanagari, Samuel J.Taylor, Luis A.Carvajal, Kith Pradhan, Boris Bartholdy, Tihomira I.Todorova, Hiroki Goto, Daqian Sun, Jiahao Chen, Jidong Shan, Yinghui Song, Cristina Montagna, Shunbin Xiong

DOI: https://doi.org/10.1016/j.ccell.2021.02.006

Background: 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. 

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