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

Christopher R. Marlein, Lyubov Zaitseva, Rachel E. Piddock, Stephen Robinson, Dylan Edwards, Manar S. Shafat, Zhigang Zhou, Matthew Lawes, Kristian M. Bowles and Stuart A. Rushworth

Key points

  • Functional mitochondria are transferred in-vivo from BMSC to the leukemic blast.

  • AML derived NOX-2 drives transfer of mitochondria via the generation of superoxide.

Abstract

Improvements in the understanding of the metabolic cross-talk between cancer and its micro-environment are expected to lead to novel therapeutic approaches. Acute myeloid leukemia (AML) cells have increased mitochondria compared to non-malignant CD34+ hematopoietic progenitor cells. Furthermore, contrary to the Warburg hypothesis, (AML) relies on oxidative phosphorylation to generate ATP. Here we report that in human AML, NOX2 generates superoxide which stimulates bone marrow stromal cells (BMSC) to AML blast transfer of mitochondria through AML derived tunnelling nanotubes. Moreover, inhibition of NOX2 was able to prevent mitochondrial transfer, increase AML apoptosis and improve NSG AML mouse survival. Although mitochondrial transfer from BMSC to non-malignant CD34+ cells occurs in response to oxidative stress, NOX2 inhibition had no detectable effect on non-malignant CD34+ cell survival. Taken together we identify tumor-specific dependence on NOX2 driven mitochondrial transfer as a novel therapeutic strategy in AML.

  • Submitted March 10, 2017.
  • Accepted July 14, 2017.