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Moore, Jamie A., Mistry, Jayna J., Hellmich, Charlotte, Horton, Rebecca H., Wojtowicz, Edyta E., Jibril, Aisha, Jefferson, Matthew, Wileman, Thomas, Beraza, Naiara, Bowles, Kristian M. 
ORCID: https://orcid.org/0000-0003-1334-4526 and Rushworth, Stuart A.
(2022)
LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation.
Journal of Clinical Investigation, 132 (5).
ISSN 0021-9738
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Abstract
The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation, and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for remaining apoptotic debris in regulating the immunologic response to and growth of solid tumors. Here, we investigated the role of macrophage LC3–associated phagocytosis (LAP) within the BM microenvironment of AML. Depletion of BM macrophages (BMMs) increased AML growth in vivo. We show that LAP is the predominate method of BMM phagocytosis of dead and dying cells in the AML microenvironment. Targeted inhibition of LAP led to the accumulation of apoptotic cells (ACs) and apoptotic bodies (ABs), resulting in accelerated leukemia growth. Mechanistically, LAP of AML-derived ABs by BMMs resulted in stimulator of IFN genes (STING) pathway activation. We found that AML-derived mitochondrial damage–associated molecular patterns were processed by BMMs via LAP. Moreover, depletion of mitochondrial DNA (mtDNA) in AML-derived ABs showed that it was this mtDNA that was responsible for the induction of STING signaling in BMMs. Phenotypically, we found that STING activation suppressed AML growth through a mechanism related to increased phagocytosis. In summary, we report that macrophage LAP of apoptotic debris in the AML BM microenvironment suppressed tumor growth.
| Item Type: | Article |
|---|---|
| Additional Information: | Funding Information: The authors wish to thank the Norwich Research Park (NRP), the Rosetrees Trust, the Big C, and the UK National Health Service (NHS). The authors also thank Allyson Tyler and Karen Ashurst from the Laboratory Medicine Department at the Norfolk and Norwich University Hospital for technical assistance. The authors also wish to thank Rachel Stanley at the Norwich Research Park (NRP) Biorepository (UK) for supporting primary tissue collection, as well as the team at the Disease Modeling Unit of the University of East Anglia for assistance with the in vivo studies. EEW is supported by a Sir Henry Welcome Postdoctoral Fellowship (213731/Z/18/Z), and JAM is supported by the Rosetrees Trust. CH is funded by a Wellcome Trust Clinical Research Fellowship. This work was supported by the Medical Research Council (MRC) project grant SAR (MR/T02934X/1). TW and NB are supported by the Biotechnology and Biological Sciences Research Council (BBSRC) Institute’s Strategic Programme Gut Microbes and Health (BB/R012490/1: BBS/E/F/000PR10353, BBS/E/F/000PR10355). The authors also acknowledge support from the BBSRC, part of UK Research and Innovation’s Core Capability Grant BB/CCG1720/1, and the National Capability (BBS/E/T/000PR9816). The authors also wish to thank Professor Irmela Jeremias for providing pCDH-luciferase-T2A-mCherry for in vivo imaging. |
| Uncontrolled Keywords: | medicine(all),sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2700 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Science > School of Biological Sciences |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health Faculty of Medicine and Health Sciences > Research Centres > Lifespan Health |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 10 Mar 2022 12:30 |
| Last Modified: | 19 Oct 2023 03:17 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/83977 |
| DOI: | 10.1172/JCI153157 |
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