美国阿尔伯特·爱因斯坦医学院Ulrich Steidl研究团队近日取得一项新成果。他们发现MDMX是一种普遍从白血病前期到急性髓细胞性白血病（AML）的转化机制。2021年3月日出版的《癌细胞》发表了这项成果。

他们报告说MDMX过表达增加了白血病前干细胞（pre-LSC）的数量和竞争优势。利用五个新构建的鼠模型，他们发现MDMX过表达会触发多种慢性/无症状的前白血病病情发展为明显的AML。转录组学和蛋白质组学研究表明，MDMX过表达意外地通过激活前LSC中的Wnt /β-Catenin信号传导发挥了这一功能。

从机理上讲，MDMX以不依赖p53的方式结合CK1α并导致β-Catenin积累。Wnt /β-Catenin抑制剂可逆转MDMX诱导的pre-LSC特性，并与MDMX-p53抑制剂协同作用。Wnt /β-Catenin信号传导与白血病前骨髓增生异常综合症患者的MDMX表达相关，并与发展为AML的风险增加相关。他们的工作将MDMX过表达确定为在不同遗传驱动的疾病亚型中普遍存在的从白血病到AML转移的机制，并揭示了Wnt /β-连环蛋白是一种非典型的MDMX驱动途径，具有预防和预防癌症的治疗潜力。

研究人员表示，MDMX在绝大多数AML患者中过表达。

附：英文原文

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

Author: 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, Guillermina Lozano, Andrea Pellagatti, Jacqueline Boultwood, Amit Verma, Ulrich Steidl

Issue&Volume: 2021-03-04

Abstract: 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, wefound that MDMX overexpression triggers progression of multiple chronic/asymptomaticpreleukemic conditions to overt AML. Transcriptomic and proteomic studies revealedthat MDMX overexpression exerts this function, unexpectedly, through activation ofWnt/β-Catenin signaling in pre-LSCs. Mechanistically, MDMX binds CK1α and leads toaccumulation of β-Catenin in a p53-independent manner. Wnt/β-Catenin inhibitors reverseMDMX-induced pre-LSC properties, and synergize with MDMX-p53 inhibitors. Wnt/β-Cateninsignaling correlates with MDMX expression in patients with preleukemic myelodysplasticsyndromes and is associated with increased risk of progression to AML. Our work identifiesMDMX overexpression as a pervasive preleukemic-to-AML transition mechanism in differentgenetically driven disease subtypes, and reveals Wnt/β-Catenin as a non-canonicalMDMX-driven pathway with therapeutic potential for progression prevention and cancerinterception.

DOI: 10.1016/j.ccell.2021.02.006

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00108-2