Alatawi Sael, Alzahrani Othman R, Alatawi Fuad A, Almazni Ibrahim A, Almotiri Alhomidi, Almsned Fahad M
Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, 47713, Tabuk, Saudi Arabia.
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Sci Rep. 2025 Mar 29;15(1):10856. doi: 10.1038/s41598-025-95738-9.
SF3B1 gene mutations are prevalent in myelodysplastic syndrome (MDS) and define a distinct disease subtype. These mutations are associated with dysregulated genes and pathways, offering potential for novel therapeutic approaches. However, the aberrant mRNA alternative splicing landscape in SF3B1-deficient MDS cells remains underexplored. In this study, we investigated the influence of SF3B1 gene alterations on the pre-mRNA splicing landscape in MDS cells using transcriptomic data from two independent MDS cohorts. we identified over 5000 significant differential alternative splicing events associated with SF3B1 mutation. This work corroborates previous studies, showing significant enrichment of MYC activity and heme metabolism in SF3B1 mutant cells. A key novel finding of this study is the identification of a gene expression signature driven by SF3B1 mutations, centered on protein post-translational modifications. Notably, we discovered aberrant alternative splicing of the tumor suppressor gene UBA7, leading to significantly reduced gene expression. This dysregulation implicates UBA7 as a critical player in MDS pathogenesis. Importantly, the clinical relevance of this finding is underscored by the observation that low UBA7 gene expression was associated with poor overall survival in chronic lymphocytic leukemia (CLL), another hematological malignancy with frequent SF3B1 mutations. Furthermore, a similar association between low UBA7 gene expression and poor survival outcomes was observed across multiple tumor types in the TCGA database, highlighting the broader implications of UBA7 dysregulation in cancer biology. These findings provide new insights into the mechanisms by which SF3B1 mutations reshape the pre-mRNA splicing landscape and drive disease pathogenesis in MDS. Furthermore, they underscore the potential of UBA7 as a biomarker to stratify SF3B1-mutant MDS and CLL patients, offering a refined approach for risk assessment and highlighting opportunities for targeted therapeutic interventions.
SF3B1基因突变在骨髓增生异常综合征（MDS）中普遍存在，并定义了一种独特的疾病亚型。这些突变与基因和通路失调相关，为新型治疗方法提供了潜力。然而，SF3B1缺陷的MDS细胞中异常的mRNA可变剪接情况仍未得到充分研究。在本研究中，我们使用来自两个独立MDS队列的转录组数据，研究了SF3B1基因改变对MDS细胞中前体mRNA剪接情况的影响。我们鉴定出了5000多个与SF3B1突变相关的显著差异可变剪接事件。这项工作证实了先前的研究，表明SF3B1突变细胞中MYC活性和血红素代谢显著富集。本研究的一个关键新发现是鉴定出了由SF3B1突变驱动的基因表达特征，其核心是蛋白质翻译后修饰。值得注意的是，我们发现肿瘤抑制基因UBA7存在异常可变剪接，导致基因表达显著降低。这种失调表明UBA7是MDS发病机制中的关键因素。重要的是，在慢性淋巴细胞白血病（CLL）（另一种频繁发生SF3B1突变的血液系统恶性肿瘤）中，低UBA7基因表达与总体生存率差相关，这一观察结果强调了这一发现的临床相关性。此外，在TCGA数据库的多种肿瘤类型中也观察到了低UBA7基因表达与不良生存结果之间的类似关联，突出了UBA7失调在癌症生物学中的更广泛影响。这些发现为SF3B1突变重塑前体mRNA剪接情况并驱动MDS疾病发病机制的机制提供了新见解。此外，它们强调了UBA7作为分层SF3B1突变的MDS和CLL患者的生物标志物的潜力，为风险评估提供了一种精细方法，并突出了靶向治疗干预的机会。
