Liu Jia, Zhang Zilu, Xu Wenbin, Jia Mingyuan, Zeng Xinyi, Wu Chengyu, Fu Ze, Xu Xiaoguang, Ye Chenjing, Wu Chao, Xu Hanzhang, Lei Hu, Wu Yingli, Yan Hua
Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of General Practice, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Blood Adv. 2025 Apr 22;9(8):1991-2005. doi: 10.1182/bloodadvances.2025015815.
Aberrant alternative splicing is one of the hallmarks of cancer and is potentially based on upregulated expression-of-splicing factors in some types of cancer. Our previous study suggested that the splicing factor RBM39 is significantly upregulated in multiple myeloma (MM) and that its upregulation is positively associated with poor prognosis. Here, we further demonstrate that the survival and proliferation of MM cells rely on RBM39 and that RBM39 knockdown inhibits the malignant growth of MM. Indisulam, a "molecular glue" that mediates the proteasomal degradation of RBM39, has potent suppressive effects on MM both in vitro and in vivo. Deletion of RBM39 results in extensively altered splicing, with mis-splicing of MEK5 verified to inhibit the malignant growth of MM. Full-length MEK5 plays a vital role in maintaining MM cell survival, whereas aberrant MEK5 isoforms with exon loss exhibit loss of function and a propensity for proteasomal degradation. Targeting RBM39 or MEK5 synergistically increases the cytotoxicity of bortezomib in MM cells via the inhibition of p65. Our study validates the specific mechanism of RBM39 in MM, providing an approach for broader targeting and optimized therapeutic strategies for MM.
异常可变剪接是癌症的标志之一，可能基于某些类型癌症中剪接因子表达上调。我们之前的研究表明，剪接因子RBM39在多发性骨髓瘤（MM）中显著上调，其上调与不良预后呈正相关。在此，我们进一步证明MM细胞的存活和增殖依赖于RBM39，RBM39基因敲低可抑制MM的恶性生长。Indisulam是一种介导RBM39蛋白酶体降解的“分子胶”，在体外和体内对MM均有强大的抑制作用。RBM39的缺失导致广泛的剪接改变，MEK5的错误剪接被证实可抑制MM的恶性生长。全长MEK5在维持MM细胞存活中起关键作用，而缺失外显子的异常MEK5异构体则表现出功能丧失和蛋白酶体降解倾向。靶向RBM39或MEK5通过抑制p65协同增加硼替佐米对MM细胞的细胞毒性。我们的研究验证了RBM39在MM中的具体机制，为MM更广泛的靶向治疗和优化治疗策略提供了一种方法。
