Aging Is a Key Driver for Adult Acute Myeloid Leukemia

ABSTRACT Aging is a progressive functional decline with increased susceptibility to human diseases. Among these age‐related diseases, adult acute myeloid leukemia (AML) is a fatal hematologic malignancy characterized by aggressive clonal expansion and arrested differentiation of myeloid progenitors. Although it is known that aging plays a crucial role in AML pathogenesis, treating this age‐related blood disease remains a huge challenge, which needs a deeper understanding of the mechanisms of aging in driving AML. This review updates recent advances on the relationship between aging and AML pathogenesis by focusing on the age‐related intrinsic and extrinsic factors. The aging of the hematopoietic system exhibits an expansion of phenotypic hematopoietic stem cells (HSCs), skewed differentiation to myeloid lineage, decreased repopulation ability, and altered clonal behaviors. We first discuss the role of aging in regulating the fate and fitness of HSCs, and summarize how aging contributes to the accumulation of genomic alterations and clonal hematopoiesis. In the following, epigenetic and metabolic alterations in hematopoietic cells and AML pathogenesis with aging are emphasized, and the aging‐related changes in extrinsic elements are also reviewed. Finally, we discuss the potential for aging intervention in treating hematopoietic malignancies. Overall, this review provides a comprehensive summary of the aging‐associated intrinsic and extrinsic factors for AML pathogenesis. Targeting these aging‐associated alterations in HSCs may provide new opportunities for AML intervention.