HYPERMETHYLATION-ASSOCIATED INACTIVATION INDICATES A TUMOR-SUPPRESSORROLE FOR P15(INK4B1)

The recently identified cyclin-dependent kinase inhibitor p15(INK4B) i s localized to a region on chromosome 9p21 frequently deleted in human tumors. Previous evidence has pointed to a related gene, p16(INK4A), the principal target of this deletion. We report that in gliomas and, to a striking degree, in leukemias, the p15 gene is commonly inactivat ed in association with promoter region hypermethylation involving mult iple sites in a 5'-CpG island. In some gliomas and all of the primary leukemias, this event occurs without alteration of the adjacent gene, p16(INK4A). In other tumors, including lung, head and neck, breast, pr ostate, and colon cancer, inactivation of p15(INK4B) occurs only rarel y and only with concomitant inactivation of p16. Aberrant methylation of p15(INK4B) is associated with transcriptional loss of this gene. Tr eatment with the demethylating agent 5-aza-2'-deoxycytidine leads to r e-expression of p15 mRNA. In selected leukemia cell lines, p15 inactiv ation correlates with known resistance to the growth-suppressive effec ts of transforming growth factor-beta. These results suggest that p15( INK4B) is inactivated selectively in leukemias and gliomas and seems t o constitute an important tumor suppressor gene loss in these neoplasm s.