Frequent and Selective Methylation ofpl5 and Deletion of Both p15 and p16 in T-Cell Acute Lymphoblastic Leukemia1

Frequent deletion of chromosome 9p2l in many cancers has suggested the presence of tumor suppressor genes in this region. Two genes mapping to 9p2l,pl5 andpl6, encode inhibitors for cyclin-dependent kinases 4 and 6.Werecently foundthatinT-cell acutelymphoblastic leukemia (T-ALL), both thepl5 and p16 genes are deleted at a high frequency, with p16 gene deletion occurring slightly more frequently than p15 gene deletion. We now show that in addition to deletion, the p15 gene is preferentially 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 38% (17 of 45) of T-ALL patients at diagnosis 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 49) of patients at diagnosis and in none (0 of 30) at relapse. The overall rates of alteration occurring in at least one allele of the p15 gene 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 majority of samples: 76% forpl5 and 67% for p16 at diagnosis. All together, more than one-half (56%) of T-ALL sam pies harbor alterations in both 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.