Interleukin-6 Facilitates Acute Myeloid Leukemia Chemoresistance via Mitofusin 1-Mediated Mitochondrial Fusion.

Acute myeloid leukemia (AML), an aggressive hematopoietic malignancy, exhibits poor prognosis and a high recurrence rate largely because of primary and secondary drug resistance. Elevated serum interleukin-6 (IL-6) levels have been observed in patients with AML and are associated with chemoresistance. Chemoresistant AML cells are highly dependent on oxidative phosphorylation (OXPHOS), and mitochondrial network remodeling is essential for mitochondrial function. However, IL-6-mediated regulation of mitochondrial remodeling and its effectiveness as a therapeutic target remain unclear. We aimed to determine the mechanisms through which IL-6 facilitates the development of chemoresistance in AML cells. IL-6 upregulated mitofusin 1 (MFN1)-mediated mitochondrial fusion, promoted OXPHOS, and induced chemoresistance in AML cells. MFN1 knockdown impaired the effects of IL-6 on mitochondrial function and chemoresistance in AML cells. In an MLL::AF9 fusion gene-induced AML mouse model, IL-6 reduced chemosensitivity to cytarabine (Ara-C), a commonly used anti-leukemia drug, accompanied by increased MFN1 expression, mitochondrial fusion, and OXPHOS status. In contrast, anti-IL-6 antibodies downregulated MFN1 expression, suppressed mitochondrial fusion and OXPHOS, enhanced the curative effects of Ara-C, and prolonged overall survival. In conclusion, IL-6 upregulated MFN1-mediated mitochondrial fusion in AML, which facilitated mitochondrial respiration, in turn, inducing chemoresistance. Thus, targeting IL-6 may have therapeutic implications in overcoming IL-6-mediated chemoresistance in AML. Implications: IL-6 treatment induces MFN1-mediated mitochondrial fusion, promotes OXPHOS, and confers chemoresistance in AML cells. Targeting IL-6 regulation in mitochondria is a promising therapeutic strategy to enhance the chemosensitivity of AML.

Citation

Diyu Hou, Xiaoming Zheng, Danni Cai, Ruolan You, Jingru Liu, Xiaoting Wang, Xinai Liao, Maoqing Tan, Liyan Lin, Jin Wang, Shuxia Zhang, Huifang Huang. Interleukin-6 Facilitates Acute Myeloid Leukemia Chemoresistance via Mitofusin 1-Mediated Mitochondrial Fusion. Molecular cancer research : MCR. 2023 Sep 12

PMID: 37698549

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