Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Department of Biomedical & Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Nucleic Acids Res. 2018 Nov 30;46(21):11357-11369. doi: 10.1093/nar/gky946.
Aberrant splicing is a hallmark of leukemias with mutations in splicing factor (SF)-encoding genes. Here we investigated its prevalence in pediatric B-cell acute lymphoblastic leukemias (B-ALL), where SFs are not mutated. By comparing these samples to normal pro-B cells, we found thousands of aberrant local splice variations (LSVs) per sample, with 279 LSVs in 241 genes present in every comparison. These genes were enriched in RNA processing pathways and encoded ∼100 SFs, e.g. hnRNPA1. HNRNPA1 3'UTR was most pervasively mis-spliced, yielding the transcript subject to nonsense-mediated decay. To mimic this event, we knocked it down in B-lymphoblastoid cells and identified 213 hnRNPA1-regulated exon usage events comprising the hnRNPA1 splicing signature in pediatric leukemia. Some of its elements were LSVs in DICER1 and NT5C2, known cancer drivers. We searched for LSVs in other leukemia and lymphoma drivers and discovered 81 LSVs in 41 additional genes. Seventy-seven LSVs out of 81 were confirmed using two large independent B-ALL RNA-seq datasets, and the twenty most common B-ALL drivers, including NT5C2, showed higher prevalence of aberrant splicing than of somatic mutations. Thus, post-transcriptional deregulation of SF can drive widespread changes in B-ALL splicing and likely contributes to disease pathogenesis.
剪接异常是具有剪接因子（SF）编码基因突变的白血病的标志。在这里，我们研究了其在儿科 B 细胞急性淋巴细胞白血病（B-ALL）中的普遍性，SF 在这些白血病中并未发生突变。通过将这些样本与正常前 B 细胞进行比较，我们发现每个样本中都存在数千种异常局部剪接变异（LSV），在 241 个基因中存在 279 个 LSV。这些基因富集在 RNA 处理途径中，并编码约 100 个 SF，例如 hnRNPA1。hnRNPA1 的 3'UTR 被最普遍地错误剪接，产生易受无意义介导的衰变影响的转录本。为了模拟这种情况，我们在 B 淋巴细胞样细胞中敲低它，并在儿科白血病中鉴定出 213 个 hnRNPA1 调控的外显子使用事件，包括 hnRNPA1 剪接特征。其一些元件是 DICER1 和 NT5C2 中的 LSV，这是已知的癌症驱动基因。我们在其他白血病和淋巴瘤驱动基因中搜索 LSV，并在 41 个额外基因中发现了 81 个 LSV。81 个 LSV 中有 77 个通过两个大型独立的 B-ALL RNA-seq 数据集得到确认，20 个最常见的 B-ALL 驱动基因，包括 NT5C2，显示出异常剪接的发生率高于体细胞突变。因此，SF 的转录后失调可能会导致 B-ALL 剪接的广泛变化，并可能有助于疾病的发病机制。
