Mitochondrial metabolism: Critical mechanisms underpinning normal hematopoietic stem cell and acute myeloid leukemia stem cell function

Abstract

AML (Acute myeloid leukemia) is an aggressive cancer of the blood and bone marrow characterized by the excessive proliferation of immature white blood cells, that disrupt normal hematopoiesis. LSCs (Leukemic stem cells) represent a subpopulation of AML cells with stem cell-like properties that drive AML initiation, progression, and relapse by evading conventional therapies and sustaining leukemic growth. Despite advances in understanding AML biology, particularly their metabolic alternations, remain poorly understood. Indeed, recent studies have shown that mitochondrial metabolism plays a pivotal role in the regulation of both normal HSCs (hematopoietic stem cells) and LSCs. In this review, we delve into the mitochondrial metabolic characteristics of normal HSCs to provide comprehensive background knowledge. Subsequently, we thoroughly analyze how the distinctive metabolic features of LSCs, highlighting the impact of these differences on cell function and survival. We also investigate the unique mechanisms of drug resistance in LSCs, explaining how these mechanisms enhance the survival of LSCs in the face of conventional treatments. Finally, we discuss emerging therapeutic strategies targeting the mitochondrial metabolism of LSCs in AML, and we discuss prospective therapeutic strategies and future research directions.

Keywords: Acute myeloid leukemia; Hematopoietic stem cell; Leukemia stem cell; Metabolism; Mitochondria; Mitochondrial quality control.