Chen Shih-Shih, Raval Aparna, Johnson Amy J, Hertlein Erin, Liu Te-Hui, Jin Victor X, Sherman Mara H, Liu Shu-Jun, Dawson David W, Williams Katie E, Lanasa Mark, Liyanarachchi Sandya, Lin Thomas S, Marcucci Guido, Pekarsky Yuri, Davuluri Ramana, Croce Carlo M, Guttridge Denis C, Teitell Michael A, Byrd John C, Plass Christoph
Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13433-8. doi: 10.1073/pnas.0906455106. Epub 2009 Jul 28.
Epigenetic alterations, including gain or loss of DNA methylation, are a hallmark of nearly every malignancy. Changes in DNA methylation can impact expression of cancer-related genes including apoptosis regulators and tumor suppressors. Because such epigenetic changes are reversible, they are being aggressively investigated as potential therapeutic targets. Here we use the Emu-TCL1 transgenic mouse model of chronic lymphocytic leukemia (CLL) to determine the timing and patterns of aberrant DNA methylation, and to investigate the mechanisms that lead to aberrant DNA methylation. We show that CLL cells from Emu-TCL1 mice at various stages recapitulate epigenetic alterations seen in human CLL. Aberrant methylation of promoter sequences is observed as early as 3 months of age in these animals, well before disease onset. Abnormally methylated promoter regions include binding sites for the transcription factor FOXD3. We show that loss of Foxd3 expression due to an NF-kappaB p50/p50:HDAC1 repressor complex occurs in TCL1-positive B cells before methylation. Therefore, specific transcriptional repression is an early event leading to epigenetic silencing of target genes in murine and human CLL. These results provide strong rationale for the development of strategies to target NF-kappaB components in CLL and potentially other B-cell malignancies.
表观遗传改变，包括DNA甲基化的增加或减少，是几乎每种恶性肿瘤的一个标志。DNA甲基化的变化会影响包括凋亡调节因子和肿瘤抑制因子在内的癌症相关基因的表达。由于这种表观遗传变化是可逆的，它们正作为潜在的治疗靶点被积极研究。在这里，我们使用慢性淋巴细胞白血病（CLL）的Emu-TCL1转基因小鼠模型来确定异常DNA甲基化的时间和模式，并研究导致异常DNA甲基化的机制。我们表明，来自不同阶段的Emu-TCL1小鼠的CLL细胞重现了人类CLL中所见的表观遗传改变。在这些动物中，早在3个月大时就观察到启动子序列的异常甲基化，远早于疾病发作。异常甲基化的启动子区域包括转录因子FOXD3的结合位点。我们表明，在甲基化之前，TCL1阳性B细胞中由于NF-κB p50/p50:HDAC1阻遏复合物导致Foxd3表达缺失。因此，特异性转录抑制是导致小鼠和人类CLL中靶基因表观遗传沉默的早期事件。这些结果为开发针对CLL及潜在其他B细胞恶性肿瘤中NF-κB成分的策略提供了有力的理论依据。
