DNMT3B7 disrupts embryonic development and accelerates lymphomagenesis

Cancer cells have an altered distribution of DNA methylation and express aberrant DNA methyltransferase 3B transcripts, which encode truncated proteins. To test if a truncated DNMT3B isoform disrupts DNA methylation in vivo, we constructed transgenic mice expressing DNMT3B7, a common truncated DNMT3B isoform in cancer cells. DNMT3B7 transgenic mice exhibit altered embryonic development, including lymphopenia, craniofacial abnormalities, and cardiac defects, similar to Dnmt3b-deficient animals, but rarely develop cancer. However, DNMT3B7 expression increases the frequency of mediastinal lymphomas in Eμ−myc animals. Eμ-myc/DNMT3B7 lymphomas have more chromosomal rearrangements, increased global methylation levels, and more locus-specific perturbations in DNA methylation patterns compared to Eμ-myc lymphomas. Our results demonstrate that a truncated DNMT3B protein can alter tumorigenesis, suggesting a similar role in human tumors. Direct comparison of DNA methylation in lymphoma samples from Eu-Myc vs Eu-Myc/Dnmt3b7 mice.

癌细胞的DNA甲基化分布发生改变，且表达异常的DNA甲基转移酶3B（DNA methyltransferase 3B, DNMT3B）转录本，此类转录本编码截短型蛋白质。为探究截短型DNMT3B同工型是否会在体内干扰DNA甲基化，我们构建了表达DNMT3B7的转基因小鼠——DNMT3B7是癌细胞中常见的截短型DNMT3B同工型。DNMT3B7转基因小鼠表现出胚胎发育异常，包括淋巴细胞减少症、颅面畸形与心脏缺陷，表型与DNMT3B缺陷型动物相似，但此类小鼠极少发生癌症。然而，在Eμ-myc小鼠中，DNMT3B7的表达会升高纵隔淋巴瘤的发生频率。相较于Eμ-myc淋巴瘤，Eμ-myc/DNMT3B7淋巴瘤存在更多染色体重排现象、更高的全基因组甲基化水平，以及更多位点特异性的DNA甲基化模式紊乱。本研究结果证实，截短型DNMT3B蛋白质可调控肿瘤发生过程，提示其在人类肿瘤中可能发挥类似作用。本研究对Eμ-Myc与Eμ-Myc/Dnmt3b7小鼠的淋巴瘤样本进行DNA甲基化水平的直接比较。