Chronic myeloid leukemia (CML) is a malignancy that evolves through a multi-step process. Alternative splicing of several genes has been linked to the progression of the disease, but involvement of alternations in splicing profiles has not been reported. RNA-seq of peripheral blood mononuclear cell (PBMC) samples characterized the differentially expressed and spliced transcripts in five CML chronic phase (CP) and five blast phase (BP) patients, and five healthy controls. Global splicing alteration analysis detected 6474 altered splicing events altered between CML and healthy samples, including many of the previously reported splicing variants and showing a more profound altered splicing deregulation in BP samples. Functional clustering of differentially spliced genes in CP revealed a preferred enrichment relating to cell signaling, while the spliceosome pathway was most overrepresented in BP samples. One differentially spliced spliceosome gene hnRNPA1 showed two splice isoforms; the longer isoform contained exon 8 was preferentially expressed in the BP patients, and the short one excluding exon 8 was specific to healthy controls. Our findings suggested that alternative splicing deregulation played a central role during the progression of CML from CP to BP, and the longer isoform of hnRNPA1 might represent a diagnostic marker and therapeutic target for CML.

中文翻译：

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转录组分析显示慢性髓细胞性白血病中hnRNPA1外显子8包含的发生率很高。

慢性粒细胞白血病（CML）是一种恶性肿瘤，它通过多步过程演变而成。几种基因的选择性剪接与疾病的进展有关，但尚未报道剪接图谱中交替出现的情况。外周血单核细胞（PBMC）样品的RNA序列表征了5例CML慢性期（CP）和5 blast阶段（BP）患者以及5例健康对照的差异表达和剪接的转录本。全局剪接变化分析检测到了6474个在CML和健康样品之间发生的剪接事件发生了变化，包括许多先前报道的剪接变体，并显示了BP样品中更深的剪接失控变化。CP中差异剪接基因的功能聚类揭示了与细胞信号传导有关的优选富集，而剪接体途径在BP样本中最多。一个差异剪接的剪接体基因hnRNPA1显示了两个剪接同工型。BP患者中优先表达包含8号外显子的较长同工型，而8号外显子除外的短同种型对健康对照组具有特异性。我们的发现表明，在CML从CP到BP的过程中，选择性剪接解除调控起着核心作用，而hnRNPA1更长的同工型可能代表了CML的诊断标记和治疗靶点。