Acute Myeloid Leukemia: Aging and Epigenetics

Abstract

Acute myeloid leukemia (AML) is an aggressive hematological disorder mainly affecting people of older age. AML initiation is primarily attributed to mutations in crucial cellular regulators such as epigenetic factors, transcription factors, and signaling genes. AML's aggressiveness and responsiveness to treatment depends on the specific cell type where leukemia first arose. Aged hematopoietic cells are often genetically and/or epigenetically altered and, therefore, present with a completely different cellular context for AML development compared to young cells. In this review, we summarize key aspects of AML development, and we focus, in particular, on the contribution of cellular aging to leukemogenesis and on current treatment options for elderly AML patients. Hematological disorders and leukemia grow exponentially with age. So far, with conventional induction therapy, many elderly patients experience a very poor overall survival rate requiring substantial social and medical costs during the relatively few remaining months of life. The global population's age is increasing rapidly without an acceptable equal growth in therapeutic management of AML in the elderly; this is in sharp contrast to the increase in successful therapies for leukemia in younger patients. Therefore, a focus on the understanding of the biology of aging in the hematopoietic system, the development of appropriate research models, and new therapeutic approaches are urged.

Keywords: acute myeloid leukemia (AML); aging; clonal hematopoiesis (CH); epigenetic; hematopoietic stem cell (HSC); mutation.

Figure 1

Cartoon scheme illustrating the effect of young and aged intracellular contexts on leukemic transformation. A leukemia-initiating event is indicated with a red star. Healthy hematopoietic stem and progenitor cells (HSPCs) (without red star) acquire a leukemia-initiating event which leads to expansion of the leukemic cells (with the red star). After diagnosis, young and aged leukemic cells are treated with the compound developed to target young leukemic cells. Young leukemic cells respond to the treatment and dye. Residual healthy HSPCs support the regeneration of the hematopoietic system. Aged leukemic cells do not respond to the same treatment due to the different intracellular genetic and/or epigenetic context and leukemia progression is not arrested. Figure created by using the resources provided by Servier Medical ART which is licensed under a Creative Commons Attribution 3.0 Unported License.