Li Yuxiang, Bai Jing, Liu Dan, Hao Jinxia, Yan Ruyu, Guo Hongjuan, Huang Yuzhi, Yu Hongtao, Leng Hao, Zhou Kecheng, Liu Minxia
School of Life Sciences, Anhui Medical University, Hefei, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
J Cell Mol Med. 2025 Jan;29(1):e70331. doi: 10.1111/jcmm.70331.
Multiple myeloma (MM) is a haematological lymphoid malignancy marked by significant morbidity due to severe complications. Despite advances in targeted therapies, including proteasome inhibitors and the BCL-2 inhibitor venetoclax, drug resistance frequently occurs, with the underlying mechanisms poorly understood. This study investigates the role of lysosome-associated protein transmembrane 5 (LAPTM5) in conferring resistance to venetoclax in relapsed MM. Using comprehensive analyses of publicly available databases and experimental validation, we demonstrated that LAPTM5 is upregulated and enhances autophagy in recurrent multiple myeloma cells, which is a key process for cell homeostasis and drug resistance. Mechanistic studies reveal that LAPTM5 facilitates autophagic flux, linking it to the cellular catabolic processes essential for survival under therapeutic stress. Our findings highlight the underexplored functions of LAPTM5 in modulating autophagy and drug resistance, we demonstrate that LAPTM5 confers resistance to venetoclax by enhancing autophagy, suggesting that targeting LAPTM5 may provide new avenues for overcoming treatment challenges. This research underscores the potential function of LAPTM5 as a therapeutic target in improving outcomes in MM treatment.
多发性骨髓瘤（MM）是一种血液系统淋巴恶性肿瘤，因严重并发症而具有较高的发病率。尽管包括蛋白酶体抑制剂和BCL-2抑制剂维奈克拉在内的靶向治疗取得了进展，但耐药性仍频繁出现，其潜在机制尚不清楚。本研究调查了溶酶体相关蛋白跨膜5（LAPTM5）在复发MM中赋予对维奈克拉耐药性的作用。通过对公开可用数据库的综合分析和实验验证，我们证明LAPTM5在复发性多发性骨髓瘤细胞中上调并增强自噬，这是细胞稳态和耐药性的关键过程。机制研究表明，LAPTM5促进自噬通量，将其与治疗应激下生存所必需的细胞分解代谢过程联系起来。我们的研究结果突出了LAPTM5在调节自噬和耐药性方面尚未充分探索的功能，我们证明LAPTM5通过增强自噬赋予对维奈克拉的耐药性，这表明靶向LAPTM5可能为克服治疗挑战提供新途径。这项研究强调了LAPTM5作为治疗靶点在改善MM治疗结果方面的潜在功能。
