Yu Han, Wu Chengli, He Jie, Zhang Yajun, Cao Qiqi, Lan Hongyan, Li Hongshan, Xu Chengyang, Chen Chen, Li Rong, Zheng Bo
Department of Oncology, Navy No.905 Hospital of PLA, Naval Medical University, Shanghai, 200052, China.
Department of Hematology, Navy Medical Center of PLA, Naval Medical University, No. 338 West Huaihai Road, Changning District, Shanghai, 200052, China.
Ann Hematol. 2025 Feb;104(2):1023-1037. doi: 10.1007/s00277-024-06163-3. Epub 2025 Jan 4.
Multiple myeloma(MM) remains incurable with high relapse and chemoresistance rates. Differentially expressed genes(DEGs) between newly diagnosed myeloma and secondary plasma cell leukemia(sPCL) were subjected to a weighted gene co-expression network analysis(WGCNA). Drug resistant myeloma cell lines were established. Seahorse XF analyzer was applied to detect the metabolism reprogramming associated with the hub gene. The metabolic relevance and the underlying mechanism of the hub gene in myeloma resistance were explored via in vitro experiments. A total of 1310 DEGs were used to construct five co-expression modules. Gene function enrichment analysis demonstrated that candidate hub genes were closely related to oxidative phosphorylation. We performed prognostic analysis and identified PSMA4 as the key hub gene related to the extramedullary invasion of myeloma. The in vitro experiments demonstrated bortezomib resistant myeloma cell lines exhibited high PSMA4 expression, improved oxidative phosphorylation activity with increased ROS level. PSMA4 knockdown re-sensitize resistant myeloma cells via suppressing oxidative phosphorylation activity. Further investigation revealed that PSMA4 induced a hypoxia state which activated the HIF-1α signaling pathway. PSMA4 induces metabolic reprogramming by improving oxidative phosphorylation activity which accounts for the hypoxia state in myeloma cell. The activated HIF-1α signaling pathway causes bortezomib resistance via promoting anti-apoptotic activity in myeloma.
多发性骨髓瘤（MM）仍然无法治愈，复发率和化疗耐药率很高。对新诊断的骨髓瘤和继发性浆细胞白血病（sPCL）之间的差异表达基因（DEG）进行加权基因共表达网络分析（WGCNA）。建立耐药骨髓瘤细胞系。应用海马XF分析仪检测与枢纽基因相关的代谢重编程。通过体外实验探索枢纽基因在骨髓瘤耐药中的代谢相关性及潜在机制。共1310个DEG用于构建5个共表达模块。基因功能富集分析表明，候选枢纽基因与氧化磷酸化密切相关。我们进行了预后分析，确定PSMA4为与骨髓瘤髓外浸润相关的关键枢纽基因。体外实验表明，硼替佐米耐药的骨髓瘤细胞系PSMA4表达高，氧化磷酸化活性提高，ROS水平升高。敲低PSMA4可通过抑制氧化磷酸化活性使耐药骨髓瘤细胞重新敏感。进一步研究发现，PSMA4诱导缺氧状态，激活HIF-1α信号通路。PSMA4通过提高氧化磷酸化活性诱导代谢重编程，这解释了骨髓瘤细胞中的缺氧状态。激活的HIF-1α信号通路通过促进骨髓瘤中的抗凋亡活性导致硼替佐米耐药。
