De novo adult acute myeloid leukemia patients’ display at diagnosis functional deregulation of redox balance correlated with molecular subtypes and overall survival

Reactive oxygen species, mainly produced by mitochondria or NAPDH oxidase, lead to oxidative stress that could contribute to the proliferation of leukemic cells or to their apoptosis during chemotherapy. In this context, we performed a prospective study in 84 newly diagnosed acute myeloid leukemia patients to characterize their redox balance and its impact on prognostic. In addition to the evaluation of the antioxidant system, we developed an original ex-vivo assay of reactive oxygen species profiles in both, leukemic and non-blastic hematopoietic cells, using mitochondrial and/or NAPDH oxidase modulators. Firstly, we showed that non-leukemic cells of acute myeloid leukemia patients displayed different reactive oxygen species profiles compared to healthy donors. This reactive oxygen species deregulation in “normal” cells from acute myeloid leukemia microenvironment was associated with antioxidant deregulation (glutathione…). Reactive oxygen species profiles of leukemic cells were significantly different among French-American-British subtypes and better-revealed acute myeloid leukemia molecular heterogeneity than reactive oxygen species at baseline. Finally, high reactive oxygen species levels in presence of both mitochondrial stress and NAPDH oxidase activators, high reduced/oxidative glutathione ratio and high thiols levels were significantly correlated with better survival independently of usual prognostic factors, in multivariate analysis. In conclusion, our study proves that leukemic cells display functional deregulations of redox balance correlated with molecular subtypes and prognosis of acute myeloid leukemia.