Murine double minute X plays a central role in leukemic transformation and may be a promising target for leukemia prevention strategies

Abstract

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 the 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 have 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 be prevented by targeting MDMX in preleukemic stem cells are discussed.