Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, China.
Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
Mol Cancer Res. 2023 Dec 1;21(12):1366-1378. doi: 10.1158/1541-7786.MCR-23-0382.
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 IL6 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, IL6-mediated regulation of mitochondrial remodeling and its effectiveness as a therapeutic target remain unclear. We aimed to determine the mechanisms through which IL6 facilitates the development of chemoresistance in AML cells. IL6 upregulated mitofusin 1 (MFN1)-mediated mitochondrial fusion, promoted OXPHOS, and induced chemoresistance in AML cells. MFN1 knockdown impaired the effects of IL6 on mitochondrial function and chemoresistance in AML cells. In an MLL::AF9 fusion gene-induced AML mouse model, IL6 reduced chemosensitivity to cytarabine (Ara-C), a commonly used antileukemia drug, accompanied by increased MFN1 expression, mitochondrial fusion, and OXPHOS status. In contrast, anti-IL6 antibodies downregulated MFN1 expression, suppressed mitochondrial fusion and OXPHOS, enhanced the curative effects of Ara-C, and prolonged overall survival. In conclusion, IL6 upregulated MFN1-mediated mitochondrial fusion in AML, which facilitated mitochondrial respiration, in turn, inducing chemoresistance. Thus, targeting IL6 may have therapeutic implications in overcoming IL6-mediated chemoresistance in AML.
IL6 treatment induces MFN1-mediated mitochondrial fusion, promotes OXPHOS, and confers chemoresistance in AML cells. Targeting IL6 regulation in mitochondria is a promising therapeutic strategy to enhance the chemosensitivity of AML.
急性髓系白血病（AML）是一种侵袭性血液恶性肿瘤，其预后较差，复发率较高，主要原因是原发性和继发性药物耐药。AML 患者的血清 IL6 水平升高，并与化疗耐药相关。耐药的 AML 细胞对氧化磷酸化（OXPHOS）高度依赖，线粒体网络重塑对于线粒体功能至关重要。然而，IL6 介导的线粒体重塑调节及其作为治疗靶点的有效性尚不清楚。我们旨在确定 IL6 促进 AML 细胞化疗耐药发展的机制。IL6 上调了线粒体融合蛋白 1（MFN1）介导的线粒体融合，促进了 OXPHOS，并诱导了 AML 细胞的化疗耐药。MFN1 敲低会损害 IL6 对 AML 细胞线粒体功能和化疗耐药的影响。在 MLL::AF9 融合基因诱导的 AML 小鼠模型中，IL6 降低了阿糖胞苷（Ara-C）的化疗敏感性，这是一种常用的抗白血病药物，同时伴随着 MFN1 表达、线粒体融合和 OXPHOS 状态的增加。相比之下，抗 IL6 抗体下调了 MFN1 的表达，抑制了线粒体融合和 OXPHOS，增强了 Ara-C 的疗效，并延长了总生存期。总之，IL6 在 AML 中上调了 MFN1 介导的线粒体融合，促进了线粒体呼吸，进而诱导了化疗耐药。因此，靶向 IL6 可能在克服 AML 中 IL6 介导的化疗耐药方面具有治疗意义。
注释：IL6，白细胞介素 6；AML，急性髓系白血病；MLL，混合谱系白血病；AF9，AF9 融合基因；MFN1，线粒体融合蛋白 1；OXPHOS，氧化磷酸化；Ara-C，阿糖胞苷。
