A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1.

A significant proportion of infant B-cell acute lymphoblastic leukemia (B-ALL) patients remains with a dismal prognosis due to yet undetermined mechanisms. We performed a comprehensive multicohort analysis of gene expression, gene fusions, and RNA splicing alterations to uncover molecular signatures potentially linked to the observed poor outcome. We identified 87 fusions with significant allele frequency across patients and shared functional impacts, suggesting common mechanisms across fusions. We further identified a gene expression signature that predicts high risk independently of the gene fusion background and includes the upregulation of the splicing factor SRRM1. Experiments in B-ALL cell lines provided further evidence for the role of SRRM1 on cell survival, proliferation, and invasion. Supplementary analysis revealed that SRRM1 potentially modulates splicing events associated with poor outcomes through protein-protein interactions with other splicing factors. Our findings reveal a potential convergent mechanism of aberrant RNA processing that sustains a malignant phenotype independently of the underlying gene fusion and that could potentially complement current clinical strategies in infant B-ALL. A multi-cohort analysis of B-ALL samples identifies a gene expression signature that predicts high risk independently of the gene fusion background and includes the upregulation of the splicing factor SRRM1.

婴儿B细胞急性淋巴细胞白血病（B - ALL）患者中有相当大比例因尚未明确的机制而预后不良。我们对基因表达、基因融合以及RNA剪接改变进行了全面的多队列分析，以揭示可能与观察到的不良结果相关的分子特征。我们在患者中鉴定出87种具有显著等位基因频率且具有共同功能影响的融合基因，这表明融合基因之间存在共同机制。我们进一步鉴定出一种基因表达特征，它能独立于基因融合背景预测高风险，并且包括剪接因子SRRM1的上调。在B - ALL细胞系中进行的实验为SRRM1在细胞存活、增殖和侵袭中的作用提供了进一步证据。补充分析显示，SRRM1可能通过与其他剪接因子的蛋白质 - 蛋白质相互作用来调节与不良结果相关的剪接事件。我们的研究结果揭示了一种异常RNA加工的潜在汇聚机制，该机制独立于潜在的基因融合维持恶性表型，并可能补充婴儿B - ALL目前的临床策略。 对B - ALL样本的多队列分析鉴定出一种基因表达特征，它能独立于基因融合背景预测高风险，并且包括剪接因子SRRM1的上调。