Splicing changes are common in cancer and are associated with dysregulated splicing factors. Here, we analyzed RNA-seq data from 323 newly diagnosed multiple myeloma (MM) patients and described the alternative splicing (AS) landscape. We observed a large number of splicing pattern changes in MM cells compared to normal plasma cells (NPC). The most common events were alterations of mutually exclusive exons and exon skipping. Most of these events were observed in the absence of overall changes in gene expression and often impacted the coding potential of the alternatively spliced genes. To understand the molecular mechanisms driving frequent aberrant AS, we investigated 115 splicing factors (SFs) and associated them with the AS events in MM. We observed that ~40% of SFs were dysregulated in MM cells compared to NPC and found a significant enrichment of SRSF1, SRSF9, and PCB1 binding motifs around AS events. Importantly, SRSF1 overexpression was linked with shorter survival in two independent MM datasets and was correlated with the number of AS events, impacting tumor cell proliferation. Together with the observation that MM cells are vulnerable to splicing inhibition, our results may lay the foundation for developing new therapeutic strategies for MM. We have developed a web portal that allows custom alternative splicing event queries by using gene symbols and visualizes AS events in MM and subgroups. Our portals can be accessed at http://rconnect.dfci.harvard.edu/mmsplicing/ and https://rconnect.dfci.harvard.edu/mmleafcutter/.
剪接变化在癌症中较为常见，通常与剪接因子调控异常相关。本研究通过对323例初诊多发性骨髓瘤（MM）患者的RNA-seq数据进行分析，描绘了选择性剪接（AS）的分子图谱。与正常浆细胞（NPC）相比，我们在MM细胞中观察到大量剪接模式改变，其中最常见的是互斥外显子变异和外显子跳跃事件。这些剪接事件大多发生在基因表达水平无明显整体变化的背景下，并常影响选择性剪接基因的编码潜能。为探究驱动频繁异常剪接的分子机制，我们研究了115个剪接因子（SFs）及其与MM中AS事件的关联。研究发现约40%的剪接因子在MM细胞中较正常浆细胞出现表达失调，并在AS事件周围区域发现SRSF1、SRSF9和PCB1结合基序的显著富集。值得注意的是，在两个独立的MM数据集中，SRSF1过表达与患者较短生存期相关，且其表达水平与AS事件数量呈正相关，同时影响肿瘤细胞增殖能力。结合MM细胞对剪接抑制具有敏感性的观察结果，本研究或可为开发多发性骨髓瘤新型治疗策略奠定基础。我们建立了可通过基因符号进行自定义选择性剪接事件查询的网络平台，该平台可可视化展示MM及其亚型中的AS事件。访问地址：http://rconnect.dfci.harvard.edu/mmsplicing/ 与 https://rconnect.dfci.harvard.edu/mmleafcutter/。
肿瘤(癌症)患者之家