Editors' ChoiceCancer

AML survives with a little help from its friends

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Science Translational Medicine  29 Jun 2016:
Vol. 8, Issue 345, pp. 345ec104
DOI: 10.1126/scitranslmed.aag2115

Strategies that have produced dramatic successes in curing many cancers, such as small molecule tyrosine kinase inhibitors and immunotherapy, have not yet improved outcomes for patients with acute myeloid leukemia (AML). Leukemia stem cells (LSCs) seem to be sheltered in the bone marrow microenvironment despite intensive chemotherapy and disease remission. In that protective niche, they can thrive, ultimately causing disease relapse and death. So how do LSCs survive despite the cellular stresses of chemotherapy? Moschoi and colleagues have identified one way that LSCs rely on their neighboring bone marrow stromal cells. They demonstrated that after exposure to the commonly used chemotherapy drugs cytarabine, etoposide, and doxorubicin, AML cells that were adherent to bone marrow stromal cells in vitro “borrowed” mitochondria from those stromal cells. The borrowed mitochondria provided an increase in oxidative phosphorylation, seeming to support recovery from chemotherapy-induced DNA damage. These mitochondria were actively transferred by endocytosis, not passively by phagocytosis. Mitochondrial transfer was blocked by treatment with the microtubular poison vincristine, an agent not usually used in AML treatment. In mouse xenografts of human AML, leukemia cells harvested from the peripheral blood after chemotherapy had acquired murine mitochondrial DNA—but not murine nuclear DNA—further demonstrating that this process is specific to mitochondria and occurs in vivo.

These findings suggest that AML treatment should be broadened to include not only the malignant cells but also the neighborhood in which they live and thrive. The mechanisms by which LSCs induce mitochondria donation from the stromal cells are unknown, but mitochondrial transfer has been demonstrated in other malignant and nonmalignant cell lines and noncancer mouse studies, so it may be a normal physiological process that cancer cells use to support their survival. Novel treatment strategies aimed at disrupting mitochondrial transfer from bone marrow stromal cells to LSCs may eventually treat AML and other cancers more effectively.

R. Moschoi et al., Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy. Blood 10.1182/blood-2015-07-655860 (2016). [Abstract]

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