Herman J G, Jen J, Merlo A, Baylin S B
Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Cancer Res. 1996 Feb 15;56(4):722-7.
The recently identified cyclin-dependent kinase inhibitor p15INK4B is localized to a region on chromosome 9p21 frequently deleted in human tumors. Previous evidence has pointed to a related gene, p16INK4A, as the principal target of this deletion. We report that in gliomas and, to a striking degree, in leukemias, the p15 gene is commonly inactivated in association with promoter region hypermethylation involving multiple sites in a 5'-CpG island. In some gliomas and all of the primary leukemias, this event occurs without alteration of the adjacent gene, p16INK4A. In other tumors, including lung, head and neck, breast, prostate, and colon cancer, inactivation of p15INK4B occurs only rarely and only with concomitant inactivation of p16. Aberrant methylation of p15INK4B is associated with transcriptional loss of this gene. Treatment with the demethylating agent 5-aza-2'-deoxycytidine leads to re-expression of p15 mRNA. In selected leukemia cell lines, p15 inactivation correlates with known resistance to the growth-suppressive effects of transforming growth factor-beta. These results suggest that p15INK4B is inactivated selectively in leukemias and gliomas and seems to constitute an important tumor suppressor gene loss in these neoplasms.
最近发现的细胞周期蛋白依赖性激酶抑制剂p15INK4B定位于人类肿瘤中经常缺失的9号染色体p21区域。先前的证据表明，相关基因p16INK4A是该缺失的主要靶点。我们报告，在神经胶质瘤中，以及在白血病中程度显著的是，p15基因通常因与5'-CpG岛中多个位点的启动子区域高甲基化相关而失活。在一些神经胶质瘤和所有原发性白血病中，这一事件发生时相邻基因p16INK4A未发生改变。在其他肿瘤中，包括肺癌、头颈癌、乳腺癌、前列腺癌和结肠癌，p15INK4B仅很少失活，且仅在p16同时失活时才会发生。p15INK4B的异常甲基化与该基因的转录缺失相关。用去甲基化剂5-氮杂-2'-脱氧胞苷处理可导致p15 mRNA重新表达。在选定的白血病细胞系中，p15失活与已知的对转化生长因子-β生长抑制作用的抗性相关。这些结果表明，p15INK4B在白血病和神经胶质瘤中被选择性失活，似乎构成了这些肿瘤中一个重要的肿瘤抑制基因缺失。
