FREQUENT AND SELECTIVE METHYLATION OF P15 AND DELETION OF BOTH P15 AND P16 IN T-CELL ACUTE LYMPHOBLASTIC-LEUKEMIA

Frequent deletion of chromosome 9p21 in many cancers has suggested the presence of tumor suppressor genes in this region. Two genes mapping to 9p21, p15 and p16, encode inhibitors for cyclin-dependent kinases 4 and 6. We recently found that in T-cell acute lymphoblastic leukemia (T-ALL), both the p15 and p16 genes are deleted at a high frequency, w ith p16 gene deletion occurring slightly more frequently than p15 gene deletion. We now show that in addition to deletion, the p15 gene is p referentially hypermethylated at a 5' CpG island, which has been shown previously to be associated with loss Of transcription of this gene. The p15 gene was methylated in 35% (17 of 45) of T-ALL patients at dia gnosis and in 22% (7 of 32) of patients at relapse. On the other hand, methylation of the p16 gene was a rare event, occurring in 4% (2 of 4 9) of patients at diagnosis and in none (0 of 30) at relapse. The over all rates of alteration occurring in at least one allele of the p15 ge ne is 84% at diagnosis and 88% at relapse, These rates are as high as, if not greater than, those for the p16 gene (80% at diagnosis and 74% at relapse). In fact, such alterations involve both alleles in the ma jority of samples: 76% for p15 and 67% for p16 at diagnosis. All toget her, more than one-half (56%) of T-ALL samples harbor alterations in b oth alleles of both p15 and p16. These results lend strong support for a role of both p15 and p16 as tumor suppressors in T-ALL.