Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia
Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia
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DOI：
10.1038/ng1521
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发表时间：
2005-03-01
期刊：
影响因子：
30.8
通讯作者：
Plass, C
中科院分区：
文献类型：
--
作者：
Yu, L;Liu, CH;Plass, C
DNA甲基化与恶性转化相关，但遗传变异性、肿瘤异质性、配对正常组织的可用性和DNA甲基化的全球评估方法所施加的限制了对人类癌症起始和进展中表观遗传事件的程度的理解以及对癌症期间经历甲基化的基因的鉴定。我们开发了一种小鼠T/自然杀伤细胞急性淋巴细胞白血病模型，该模型总是在多克隆淋巴细胞扩增之前，以确定异常启动子DNA甲基化和随后的基因沉默可能如何促进白血病转化。我们使用限制性标记基因组扫描与这个小鼠模型的白血病前期可重复地进展为白血病，以表明特定的基因组甲基化仅与白血病阶段相关，而不是随机的。我们还确定了Idb 4作为一个假定的肿瘤抑制基因，在大多数小鼠和人类白血病中甲基化，但只有少数其他人类癌症。
DNA methylation is associated with malignant transformation, but limitations imposed by genetic variability, tumor heterogeneity, availability of paired normal tissues and methodologies for global assessment of DNA methylation have limited progress in understanding the extent of epigenetic events in the initiation and progression of human cancer and in identifying genes that undergo methylation during cancer. We developed a mouse model of T/natural killer acute lymphoblastic leukemia that is always preceded by polyclonal lymphocyte expansion to determine how aberrant promoter DNA methylation and consequent gene silencing might be contributing to leukemic transformation. We used restriction landmark genomic scanning with this mouse model of preleukemia reproducibly progressing to leukemia to show that specific genomic methylation is associated with only the leukemic phase and is not random. We also identified Idb4 as a putative tumor-suppressor gene that is methylated in most mouse and human leukemias but in only a minority of other human cancers.