Li Yinghua, Nagai Hirokazu, Ohno Toshihito, Yuge Masaaki, Hatano Sonoko, Ito Etsuro, Mori Naoyoshi, Saito Hidehiko, Kinoshita Tomohiro
First Department of Internal Medicine, and the First Department of Pathology, Nagoya University School of Medicine, Nagoya, Japan.
Blood. 2002 Oct 1;100(7):2572-7. doi: 10.1182/blood-2001-11-0026.
The cyclin-dependent kinase inhibitor p57(KIP2) is thought to be a potential tumor suppressor gene (TSG). The present study examines this possibility. We found that the expression of p57(KIP2) gene is absent in various hematological cell lines. Exposing cell lines to the DNA demethylating agent 5-aza-2'-deoxycytidine restored p57(KIP2) gene expression. Bisulfite sequencing analysis of its promoter region showed that p57(KIP2) DNA was completely methylated in cell lines that did not express the p57(KIP2) gene. Thus, DNA methylation of its promoter might lead to inactivation of the p57(KIP2) gene. DNA methylation of this region is thought to be an aberrant alteration, since DNA was not methylated in normal peripheral blood mononuclear cells or in reactive lymphadenitis. Methylation-specific polymerase chain reaction analysis found frequent DNA methylation of the p57(KIP2) gene in primary diffuse large B-cell lymphoma (54.9%) and in follicular lymphoma (44.0%), but methylation was infrequent in myelodysplastic syndrome and adult T-cell leukemia (3.0% and 2.0%, respectively). These findings directly indicate that the profile of the p57(KIP2) gene corresponds to that of a TSG.
细胞周期蛋白依赖性激酶抑制剂p57（KIP2）被认为是一种潜在的肿瘤抑制基因（TSG）。本研究探讨了这种可能性。我们发现，p57（KIP2）基因在各种血液学细胞系中均无表达。将细胞系暴露于DNA去甲基化剂5-氮杂-2'-脱氧胞苷可恢复p57（KIP2）基因的表达。对其启动子区域进行亚硫酸氢盐测序分析表明，在不表达p57（KIP2）基因的细胞系中，p57（KIP2）DNA完全甲基化。因此，其启动子的DNA甲基化可能导致p57（KIP2）基因失活。该区域的DNA甲基化被认为是一种异常改变，因为在正常外周血单个核细胞或反应性淋巴结炎中DNA未发生甲基化。甲基化特异性聚合酶链反应分析发现，原发性弥漫性大B细胞淋巴瘤（54.9%）和滤泡性淋巴瘤（44.0%）中p57（KIP2）基因存在频繁的DNA甲基化，但在骨髓增生异常综合征和成人T细胞白血病中甲基化较少见（分别为3.0%和2.0%）。这些发现直接表明p57（KIP2）基因的特征与肿瘤抑制基因相符。
