M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism

Isabel Weinhäuser, Diego A. Pereira-Martins, Luciana Y. Almeida, Jacobien R. Hilberink, Douglas R.A. Silveira, Lynn Quek, Cesar Ortiz, Cleide L. Araujo, Thiago M. Bianco, Antonio Lucena-Araujo, Jose Mauricio Mota, Shanna M. Hogeling, Dominique Sternadt, Nienke Visser, Arjan Diepstra, Emanuele Ammatuna, Gerwin Huls, Eduardo M. Rego*, Jan Jacob Schuringa*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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It is increasingly becoming clear that cancers are a symbiosis of diverse cell types and tumor clones. Combined single-cell RNA sequencing, flow cytometry, and immunohistochemistry studies of the innate immune compartment in the bone marrow of patients with acute myeloid leukemia (AML) reveal a shift toward a tumor-supportive M2-polarized macrophage landscape with an altered transcriptional program, with enhanced fatty acid oxidation and NAD+ generation. Functionally, these AML-associated macrophages display decreased phagocytic activity and intra–bone marrow coinjection of M2 macrophages together with leukemic blasts strongly enhances in vivo transformation potential. A 2-day in vitro exposure to M2 macrophages results in the accumulation of CALRlow leukemic blast cells, which are now protected against phagocytosis. Moreover, M2-exposed “trained” leukemic blasts display increased mitochondrial metabolism, in part mediated via mitochondrial transfer. Our study provides insight into the mechanisms by which the immune landscape contributes to aggressive leukemia development and provides alternatives for targeting strategies aimed at the tumor microenvironment.

Original languageEnglish
Article numbereadf8522
Number of pages21
JournalScience Advances
Issue number15
Publication statusPublished - 14-Apr-2023

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