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Diversity in Macrophage Function Among LC3-Associated Phagocytosis of AML Bone Marrow

By: Vanessa A. Carter, BS
Posted: Tuesday, April 26, 2022

Stuart A. Rushworth, PhD, of Norwich Medical School, University of East Anglia, United Kingdom, and colleagues attempted to determine the role of macrophage LC3–mediated phagocytosis within the bone marrow microenvironment of patients with acute myeloid leukemia (AML). Published in the Journal of Clinical Investigation, these results revealed that tumor growth appeared to be suppressed by LC3-mediated phagocytosis of apoptotic debris within the bone marrow, and the diversity of immune cell function was entirely dependent on the tumor microenvironment.

“Patients often relapse following treatment for cancer, because small amounts of disease remain despite chemotherapy,” mentioned Dr. Rushworth in an institutional press release. “Our research reveals that targeting this biological phenomenon could help eradicate the leukemia from the bone marrow.”

Nonobese diabetic SCID Il2rg-knockout mice, C57BL/6J mice, Atg16L1E230fl/fl Cre-positive mice, and LC3-associated phagocytosis-deficient mice were obtained from multiple laboratories. Malignant and nonmalignant hematopoietic cells were obtained from Norfolk and Norwich University Hospital. CD34-positive hematopoietic stem cells and AML cells were isolated via density-gradient centrifugation, and apoptosis was induced in cells with cytosine arabinoside.

LC3-associated phagocytosis was identified as the predominant method of bone marrow macrophage phagocytosis of dead and dying cells among the AML microenvironment. The targeted inhibition of LC3-associated phagocytosis induced the accumulation of apoptotic cells and bodies, eventually resulting in accelerated growth of leukemia. Notably, the phagocytosis of AML-derived apoptotic bodies by bone marrow macrophages influenced the activation of the stimulator of interferon genes (STING) pathway.

Additionally, it was discovered that molecular patterns of AML-derived mitochondrial damage were processed by these bone marrow macrophages via LC3-associated phagocytosis. Furthermore, the depletion of mitochondrial DNA among AML-derived apoptotic bodies demonstrated that this genetic material mediated the induction of STING signaling in bone marrow macrophages. Of note, STING activation was observed to suppress the growth of AML via a mechanism related to heightened phagocytosis.

Disclosure: The study authors reported no conflicts of interest.


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