Rationale for targeting deregulated metabolic pathways as a therapeutic strategy in acute myeloid leukemia

Abstract

Metabolic reprogramming is a common cancer cell phenotype as it sustains growth and proliferation. Targeting metabolic activities offers a wide range of therapeutic possibilities which are applicable to acute myeloid leukemia (AML). Indeed, in addition to the IDH1/2-mutated AML model which established the proof-of-concept for specifically targeting metabolic adaptations in AML, several recent reports have expanded the scope of such strategies in these diseases. This review highlights recent findings on metabolic deregulation in AML and summarizes their implications in leukemogenesis. Acute myeloid leukemias (AMLs) are characterized by abnormal proliferation/survival of hematopoietic progenitors blocked in their differentiation. Recent advances in AML biology, especially in the field of their mutational landscape led to the development of targeted therapies (1). It was unexpected however that the targeting of metabolic pathways could become a potent therapeutic strategy for AML, since such deregulations are highly common in various cancer cells (2-4). However, an improved understanding of the implication of metabolism deregulation in leukemogenesis has led to this renewed interest. The identification of IDH1/2 mutations in AML cells represented the proof-of-concept that deciphering metabolic abnormalities could lead to therapeutic applications in AML. These mutations lead to the abnormal conversion of α-ketoglutarate (α-KG) to (R)-2-hydroxyglutarate [(R)-2HG] which acts as an oncometabolite by inhibiting functions of α-KG-dependent enzymes such as TET family (5). These mutations induce therefore alterations in the pattern of histone modifications and aberrant DNA methylation (6) but have also significant impact on cellular metabolism such as inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain (ETC) (7) or increased glutamine dependency of AML cells for survival (8). Targeting IDH1/2 mutations in AML is a promising metabolic targeted therapy since inhibitors of mutant-IDH1/2 enzymes induce hematological responses in patients with relapsed/refractory AML by promoting the differentiation of leukemic cells (9, 10). As finding a good therapeutic window between cancer cells and normal cells for the safe administration of new compounds remains a major challenge in the development of therapies, targeting metabolic addictions which are specific of leukemic cells or mechanisms underlying these processes clearly represent a feasible option that may work as an AML therapy. However, metabolism also regulates key processes in normal cells, including hematopoiesis. This review will therefore highlight the implication of metabolism in normal hematopoiesis and then will focus on the pathways recently reported to be deregulated and potentially targetable in AML.