BACKGROUND In cancer, normal epigenetic patterns are disturbed and contribute to gene expression changes, disease onset, and progression. The cancer epigenome is composed of the epigenetic patterns present in the tumor-initiating cell at the time of transformation, and the tumor-specific epigenetic alterations that are acquired during tumor initiation and progression. The precise dissection of these two components of the tumor epigenome will facilitate a better understanding of the biological mechanisms underlying malignant transformation. Chronic lymphocytic leukemia (CLL) originates from differentiating B cells, which undergo extensive epigenetic programming. This poses the challenge to precisely determine the epigenomic ground state of the cell-of-origin in order to identify CLL-specific epigenetic aberrations. METHODS We developed a linear regression model, methylome-based cell-of-origin modeling (Methyl-COOM), to map the cell-of-origin for individual CLL patients based on the continuum of epigenomic changes during normal B cell differentiation. RESULTS Methyl-COOM accurately maps the cell-of-origin of CLL and identifies CLL-specific aberrant DNA methylation events that are not confounded by physiologic epigenetic B cell programming. Furthermore, Methyl-COOM unmasks abnormal action of transcription factors, altered super-enhancer activities, and aberrant transcript expression in CLL. Among the aberrantly regulated transcripts were many genes that have previously been implicated in T cell biology. Flow cytometry analysis of these markers confirmed their aberrant expression on malignant B cells at the protein level. CONCLUSIONS Methyl-COOM analysis of CLL identified disease-specific aberrant gene regulation. The aberrantly expressed genes identified in this study might play a role in immune-evasion in CLL and might serve as novel targets for immunotherapy approaches. In summary, we propose a novel framework for in silico modeling of reference DNA methylomes and for the identification of cancer-specific epigenetic changes, a concept that can be broadly applied to other human malignancies.

中文翻译：

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基于甲基化的起源细胞模型（Methyl-COOM）可识别CLL中免疫调节分子的异常表达。

背景技术在癌症中，正常的表观遗传模式被打乱并且有助于基因表达的改变，疾病的发作和发展。癌症表观基因组由转化时肿瘤起始细胞中存在的表观遗传模式以及在肿瘤起始和进展过程中获得的肿瘤特异性表观遗传变化组成。肿瘤表观基因组的这两个组成部分的精确解剖将有助于更好地了解恶性转化背后的生物学机制。慢性淋巴细胞性白血病（CLL）源自分化B细胞，该B细胞经过广泛的表观遗传程序设计。这对精确确定起源细胞的表观基因基态以鉴定CLL特异的表观遗传畸变提出了挑战。方法我们开发了线性回归模型，即基于甲基化组的起源细胞模型（Methyl-COOM），以基于正常B细胞​​分化过程中表观基因组变化的连续性来绘制单个CLL患者的起源细胞。结果Methyl-coom准确地绘制了CLL的起源细胞，并鉴定了CLL特异的异常DNA甲基化事件，这些事件不会被生理性表观遗传B细胞编程所混淆。此外，甲基-COOM揭示了CLL中转录因子的异常作用，改变的超级增强子活性和异常的转录表达。在异常调节的转录物中，有许多以前与T细胞生物学有关的基因。这些标记的流式细胞仪分析证实了它们在蛋白质水平上在恶性B细胞上的异常表达。结论CLL的甲基COOM分析确定了疾病特异性异常基因调控。在这项研究中确定的异常表达基因可能在CLL的免疫逃避中起作用，并且可以作为免疫疗法的新靶标。总而言之，我们提出了一种用于参考DNA甲基化组计算机模拟和鉴定特定于癌症的表观遗传学变化的新颖框架，该概念可以广泛应用于其他人类恶性肿瘤。