Metabolism and the leukemic stem cell

Abstract

Acute leukemias are clonal disorders of hematopoiesis wherein a leukemic stem cell (LSC) acquires mutations that confer the capacity for unlimited self-renewal, impaired hematopoietic differentiation, and enhanced proliferation to the leukemic clone. Many recent advances in understanding the biology of leukemia have come from studies defining specific genetic and epigenetic abnormalities in leukemic cells. Three recent articles, however, further our understanding of leukemia biology by elucidating specific abnormalities in metabolic pathways in leukemic hematopoiesis. These studies potentially converge on the concept that modulation of reactive oxygen species (ROS) abundance may influence the pathogenesis and treatment of acute myeloid leukemia (AML).

Figure 1.

ROS, IDH1/2 mutations, and iron chelation therapy in normal and leukemic hematopoiesis. In normal hematopoiesis, the HSC resides in a niche characterized by a low partial pressure of oxygen (PO₂) and elevated HIF1-α. Myeloid differentiation of HSCs is triggered, in part, by increased PO₂ and increased ROS. A leukemia is thought to be a newly formed hematopoietic tissue initiated by a few LSCs. LSCs derived from either normal HSCs or more restricted multipotent progenitors (MPPs) as a result of genetic abnormalities. LSCs from AML patients may differentiate in response to a temporary increase in ROS caused by iron chelators. At the same time, mutations in the metabolic enzymes IDH1/2 observed in some AML patients may result in increased ROS and HIF-1. Mutations impair the normal enzymatic activity of IDH1/2, which is to create NAD(P)H and α-KG, and increase production of the oncometabolite 2-HG. 2-HG is thought to increase ROS concentrations. In addition, decreased abundance of α-KG results in reduced α-KG–mediated inhibition of proline hydroxylases; this facilitates increased HIF-1α stability.