{"title":"Integrative alternative splicing analysis reveals new prognosis signature in B-cell acute lymphoblastic leukemia.","authors":"Zhiyi Zhuo, Junfei Wang, Yonglei Zhang, Guoyu Meng","doi":"10.7150/ijbs.98899","DOIUrl":null,"url":null,"abstract":"<p><p>The dysregulation of alternative splicing (AS) is increasingly recognized as a pivotal player in the pathogenesis, progression, and treatment resistance of B-cell acute lymphoblastic leukemia (B-ALL). Despite its significance, the clinical implications of AS events in B-ALL remain largely unexplored. This study developed a prognostic model based on 18 AS events (18-AS), derived from a meticulous integration of bioinformatics methodologies and advanced machine learning algorithms. The 18-AS signature observed in B-ALL distinctly categorized patients into different groups with significant differences in immune infiltration, V(D)J rearrangement, drug sensitivity, and immunotherapy outcomes. Patients classified within the high 18-AS group exhibited lower immune infiltration scores, poorer chemo- and immune-therapy responses, and worse overall survival, underscoring the model's potential in refining therapeutic strategies. To validate the clinical applicability of the 18-AS, we established an SF-AS regulatory network and identified candidate drugs. More importantly, we conducted in vitro cell proliferation assays to confirm our analysis, demonstrating that the High-18AS cell line (SUP-B15) exhibited significantly enhanced sensitivity to Dasatinib, Dovitinib, and Midostaurin compared to the Low-18AS cell line (REH). These findings reveal AS events as novel prognostic biomarkers and therapeutic targets, advancing personalized treatment strategies in B-ALL management.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"20 11","pages":"4496-4512"},"PeriodicalIF":8.2000,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380455/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Biological Sciences","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.7150/ijbs.98899","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The dysregulation of alternative splicing (AS) is increasingly recognized as a pivotal player in the pathogenesis, progression, and treatment resistance of B-cell acute lymphoblastic leukemia (B-ALL). Despite its significance, the clinical implications of AS events in B-ALL remain largely unexplored. This study developed a prognostic model based on 18 AS events (18-AS), derived from a meticulous integration of bioinformatics methodologies and advanced machine learning algorithms. The 18-AS signature observed in B-ALL distinctly categorized patients into different groups with significant differences in immune infiltration, V(D)J rearrangement, drug sensitivity, and immunotherapy outcomes. Patients classified within the high 18-AS group exhibited lower immune infiltration scores, poorer chemo- and immune-therapy responses, and worse overall survival, underscoring the model's potential in refining therapeutic strategies. To validate the clinical applicability of the 18-AS, we established an SF-AS regulatory network and identified candidate drugs. More importantly, we conducted in vitro cell proliferation assays to confirm our analysis, demonstrating that the High-18AS cell line (SUP-B15) exhibited significantly enhanced sensitivity to Dasatinib, Dovitinib, and Midostaurin compared to the Low-18AS cell line (REH). These findings reveal AS events as novel prognostic biomarkers and therapeutic targets, advancing personalized treatment strategies in B-ALL management.
人们越来越认识到,替代剪接(AS)失调是 B 细胞急性淋巴细胞白血病(B-ALL)发病、进展和耐药性的关键因素。尽管其意义重大,但B-ALL中AS事件的临床影响在很大程度上仍未得到探讨。本研究基于18个AS事件(18-AS)建立了一个预后模型,该模型是通过对生物信息学方法和先进的机器学习算法进行细致整合而得出的。在B-ALL中观察到的18-AS特征将患者分为不同的组别,这些组别在免疫浸润、V(D)J重排、药物敏感性和免疫治疗结果方面存在显著差异。被归入高18-AS组的患者免疫浸润评分较低,化疗和免疫治疗反应较差,总生存率较低,这凸显了该模型在完善治疗策略方面的潜力。为了验证18-AS的临床适用性,我们建立了一个SF-AS调控网络,并确定了候选药物。更重要的是,我们进行了体外细胞增殖试验来证实我们的分析,结果表明与低18-AS细胞系(REH)相比,高18-AS细胞系(SUP-B15)对达沙替尼、多韦替尼和米多司林的敏感性明显增强。这些发现揭示了作为新型预后生物标志物和治疗靶点的AS事件,从而推进了B-ALL管理中的个性化治疗策略。
期刊介绍:
The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.