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.