Background: Vast transcriptomics and epigenomics changes are characteristic of human cancers including leukemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken. A striking exemplar of targeted remission induction occurs in chronic myeloid leukemia (CML) following tyrosine kinase inhibitor (TKI) therapy. Methods: Using RNA sequencing and whole-genome bisulfite sequencing, we profiled samples from chronic-phase CML patients at diagnosis and remission, and compared these to healthy donors. Results: Remarkably, our analyses revealed that abnormal splicing distinguishes remission samples from normal controls. This phenomenon is independent of the TKI drug used and in striking contrast to the normalisation of gene expression and DNA methylation patterns. Most remarkable are the high intron retention (IR) levels that even exceed those observed in the diagnosis samples. Increased IR affects cell cycle regulators at diagnosis and splicing regulators at remission. We show that aberrant splicing in CML is associated with reduced expression of specific splicing factors, histone modifications and reduced DNA methylation. Conclusions: Our results provide novel insights into the changing transcriptomic and epigenomic landscapes of CML patients during remission. The conceptually unanticipated observation of widespread aberrant alternative splicing after remission induction warrants further exploration. These results have broad implications for studying CML relapse and treating minimal residual disease.

中文翻译：

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在慢性粒细胞白血病患者中尽管分子缓解了广泛的异常剪接

背景：大量的转录组学和表观基因组学变化是包括白血病在内的人类癌症的特征。缓解时，我们认为这些变化已正常化，因此组学特征与健康个体相似。但是，尚未对癌症缓解进行深入的转录组学和表观基因组分析。在酪氨酸激酶抑制剂（TKI）治疗后的慢性粒细胞白血病（CML）中，出现了明显的靶向缓解诱导例子。方法：使用RNA测序和全基因组亚硫酸氢盐测序，我们对慢性期CML患者在诊断和缓解时的样本进行了分析，并将其与健康供体进行了比较。结果：值得注意的是，我们的分析表明异常剪接可将缓解样品与正常对照区分开。这种现象与所用的TKI药物无关，与基因表达和DNA甲基化模式的正常化形成鲜明对比。最引人注目的是高内含子保留（IR）水平，甚至超过诊断样本中观察到的水平。IR升高会在诊断时影响细胞周期调节剂，在缓解时会影响剪接调节剂。我们显示，CML中的异常剪接与特定剪接因子的减少表达，组蛋白修饰和DNA甲基化减少有关。结论：我们的结果为缓解期间CML患者的转录组和表观基因组格局的变化提供了新颖的见解。缓解诱导后广泛异常的替代剪接的概念上未预料到的观察值得进一步探索。