急性髓系白血病（AML）是由于包括无症状克隆造血在内的异常造血前状态导致的致命性疾病。遗传变异的积累是白血病转化的原因之一。然而，非遗传因素，包括特定基因的过度表达，也有助于前癌性到癌性的过渡。其中，p53抑制剂Murine Double Minute X (MDMX) 在白血病发生中扮演着至关重要的角色。MDMX广泛地在绝大多数AML病例中过度表达，包括在造血干/祖细胞（HSPC）水平上。最近，在骨髓增殖异常综合征患者的HSPC中显示高表达的MDMX与白血病转化有关，临床前研究证明MDMX过度表达加速了前癌性小鼠模型的转化，包括克隆造血模型。通过激活细胞内p53活性，MDMX抑制显示出抗白血病作用。但是，MDMX在引发白血病转化中的分子机制非常复杂。在疾病的进展过程中，既涉及到p53依赖性机制，也涉及到独立的机制。本文讨论了MDMX的典型和非典型功能以及这些功能如何参与维持、扩张和向恶性进展的前癌性干细胞。此外，本文还讨论了如何通过靶向前癌性干细胞中的MDMX可能预防白血病转化的策略。版权所有©2023 Elsevier Inc. 发布。

Acute myeloid leukemia (AML) is a fatal disease resulting from preleukemic hematopoietic conditions including asymptomatic clonal hematopoiesis. The accumulation of genetic changes is one of the causes of leukemic transformation. However, nongenetic factors including the overexpression of specific genes also contribute to preleukemic to leukemic transition. Among them, the p53 inhibitor Murine Double Minute X (MDMX) plays crucial roles especially in leukemia initiation. MDMX is broadly overexpressed in vast majority of AML cases, including in hematopoietic stem/progenitor cell (HSPC) level. Recently, high expression of MDMX in HSPC has been shown to be associated with leukemic transformation in patients with myelodysplastic syndromes, and preclinical studies demonstrated that MDMX overexpression accelerates the transformation of preleukemic murine models, including models of clonal hematopoiesis. MDMX inhibition, through activation of cell-intrinsic p53 activity, shows antileukemic effects. However, the molecular mechanisms of MDMX in provoking leukemic transformation are complicated. Both p53-dependent and independent mechanisms are involved in the progression of the disease. This review discusses the canonical and noncanonical functions of MDMX and how these functions are involved in the maintenance, expansion, and progression to malignancy of preleukemic stem cells. Moreover, strategies on how leukemic transformation could possibly be prevented by targeting MDMX in preleukemic stem cells are discussed.Copyright © 2023. Published by Elsevier Inc.