M1 macrophage-derived exosomes alleviate leukemia by causing mitochondrial dysfunction

Acute myeloid leukemia (AML) is one type of blood cancer that initially has a high cure rate but frequently relapses and leading to death. Therefore, there is an urgent need for innovative AML treatments. The leukemia C1498 cells were co-cultured with M1 macrophage-derived exosomes (M1-exo), and the proliferation and apoptosis of C1498 cells were investigated using CCK-8 and flow cytometry, respectively. qPCR and Western blot were applied to determine the PGAM5 expression in M1-exo treated C1498 cells. The role of M1-exo-derived PGAM5 in mitochondria was examined via fluorescence staining. The anti-inflammatory effects of M1-exo-derived PGAM5 and M1-exo were evaluated by flow cytometry, HE staining, and immunohistochemistry in xenograft and nude mouse tumorigenic models. M1-exo exhibited a potent capability to attenuate C1498 cell proliferation, and induce cell apoptosis. In vivo experimentation demonstrated that administration of M1-exo led to a reduction in leukocyte count, alleviated inflammatory infiltration, decreased liver and spleen weights, and significantly diminished tumor size. PGAM5 was elevated in M1-exo, and knockdown of PGAM5 in C1498 cells and M1-exo enhanced proliferation and reduced apoptosis in C1498 cells. Concurrently, M1-exo-derived PGAM5 decreased mitochondrial membrane potential and increased calcium influx in vitro. In vivo, studies showed that knockdown of PGAM5 in M1-exo elevated liver and spleen weights, augmented tumor size, and intensified hepatic inflammatory infiltration. Our study reveals that M1-exo induces mitochondrial dysfunction against leukemia through PGAM5.