Deferasirox selectively induces cell death in the clinically relevant population of leukemic CD34+CD38- cells through iron chelation, induction of ROS, and inhibition of HIF1α expression

Despite a high remission rate after therapy, only 40-50% of acute myeloid leukemia (AML) patients survive 5 years after diagnosis. The main cause of treatment failure is thought to be insufficient eradication of CD34(+)CD38(-) AML cells. In order to induce preferential cell death in CD34(+)CD38(-) AML cells, two separate events may be necessary: (1) inhibition of survival signals such as nuclear factor kappa-beta (NF-kappa B) and (2) induction of stress responses such as the oxidative stress response. Therefore, regimens that mediate both effects may be favorable. Deferasirox is a rationally designed oral iron chelator mainly used to reduce chronic iron overload in patients who receive long-term blood transfusions. Our study revealed that clinically relevant concentrations of deferasirox are cytotoxic in vitro to AML progenitor cells, but even more potent against the more primitive CD34(+)CD38(-) cell population. In addition, we found that deferasirox exerts its effect, at least in part, by inhibiting the NF-kappa B/hypoxia-induced factor 1-alpha (HIF1 alpha) pathway and by elevating reactive oxygen species levels. We believe that, pending further characterization, deferasirox can be considered as a potential therapeutic agent for eradicating CD34(+)CD38(-) AML cells. (C) 2018 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.