Haney Staci L, Upchurch Garland M, Opavska Jana, Klinkebiel David, Appiah Adams Kusi, Smith Lynette M, Heavican Tayla B, Iqbal Javeed, Joshi Shantaram, Opavsky Rene
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA.
Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA.
Sci Rep. 2016 Sep 28;6:34222. doi: 10.1038/srep34222.
Cytosine methylation of DNA is an epigenetic modification involved in the repression of genes that affect biological processes including hematopoiesis. It is catalyzed by DNA methyltransferases, one of which -DNMT3A- is frequently mutated in human hematologic malignancies. We have previously reported that Dnmt3a inactivation in hematopoietic stem cells results in chronic lymphocytic leukemia (CLL) and CD8-positive peripheral T cell lymphomas (PTCL) in EμSRα-tTA;Teto-Cre;Dnmt3a; Rosa26LOXP (Dnmt3a) mice. The extent to which molecular changes overlap between these diseases is not clear. Using high resolution global methylation and expression analysis we show that whereas patterns of methylation and transcription in normal B-1a cells and CD8-positive T cells are similar, methylomes and transcriptomes in malignant B-1a and CD8+ T cells are remarkably distinct, suggesting a cell-type specific function for Dnmt3a in cellular transformation. Promoter hypomethylation in tumors was 10 times more frequent than hypermethylation, three times more frequent in CLL than PTCL and correlated better with gene expression than hypermethylation. Cross-species molecular comparison of mouse and human CLL and PTCL reveals significant overlaps and identifies putative oncogenic drivers of disease. Thus, Dnmt3a mice can serve as a new mouse model to study CLL and PTCL in relevant physiological settings.
DNA的胞嘧啶甲基化是一种表观遗传修饰，参与对影响包括造血作用在内的生物学过程的基因的抑制。它由DNA甲基转移酶催化，其中之一——DNMT3A——在人类血液系统恶性肿瘤中经常发生突变。我们之前报道过，在EμSRα-tTA;Teto-Cre;Dnmt3a; Rosa26LOXP（Dnmt3a）小鼠中，造血干细胞中的Dnmt3a失活会导致慢性淋巴细胞白血病（CLL）和CD8阳性外周T细胞淋巴瘤（PTCL）。这些疾病之间分子变化的重叠程度尚不清楚。通过高分辨率全基因组甲基化和表达分析，我们发现，虽然正常B-1a细胞和CD8阳性T细胞中的甲基化和转录模式相似，但恶性B-1a细胞和CD8+ T细胞中的甲基化组和转录组却明显不同，这表明Dnmt3a在细胞转化中具有细胞类型特异性功能。肿瘤中的启动子低甲基化比高甲基化频繁10倍，在CLL中比PTCL频繁3倍，并且与基因表达的相关性比高甲基化更好。对小鼠和人类CLL及PTCL进行跨物种分子比较，发现了显著的重叠，并确定了疾病的假定致癌驱动因素。因此，Dnmt3a小鼠可作为一种新的小鼠模型，用于在相关生理环境中研究CLL和PTCL。
