NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts

Improvements in the understanding of the metabolic cross-talk between cancer and itsmicroenvironment are expected to lead to novel therapeutic approaches. Acute myeloid leukemia (AML) cells have increased mitochondria compared with nonmalignant CD34(+) hematopoietic progenitor cells. Furthermore, contrary to the Warburg hypothesis, AML relies on oxidative phosphorylation to generate adenosine triphosphate. Here we report that in human AML, NOX2generates superoxide, which stimulates bonemarrow stromal cells (BMSC) toAMLblast transfer of mitochondria through AML-derived tunneling nanotubes. Moreover, inhibition of NOX2 was able to prevent mitochondrial transfer, increase AML apoptosis, and improve NSG AMLmouse survival. Although mitochondrial transfer fromBMSC to nonmalignant CD34(+) cells occurs in response tooxidativestress, NOX2inhibitionhadnodetectable effectonnonmalignantCD34(+) cellsurvival. Taken together, we identify tumor-specific dependence on NOX2-driven mitochondrial transfer as a novel therapeutic strategy in AML.