Inactivation of the cyclin-dependent kinase inhibitor p15(INK4b) by deletion and de novo methylation with independence of p16(INK4 alpha) alterations in murine primary T-cell lymphomas

A wide panel of murine induced T-cell lymphomas have been analysed for p16(INK4a) Or p15(INK4b) alterations, Only one gamma-radiation-induced lymphoma showed p16(INK4a) homozygous deletion and no other intragenic mutations were found in these INK4 genes, However, de novo methylation of the 5' CpG islands of the murine p15(INK4b) and p16(INK4a) genes was found to be highly frequent, While p16(INK4a) hypermethylation was found in 36% of the neutron-radiation-induced lymphomas and 15% of the gamma-radiation-induced lymphomas, de novo methylation of p15(INK4b) occurs in 88% and 42% of these tumors respectively, correlating with deficient expression of the corresponding mRNA and allelic losses in the p15(INK4b) and p16(INK4a) chromosome location, These data represent, to our knowledge, the first report on the significant involvement of hypermethylation of these INK4 genes in murine primary tumors, Moreover, they show the importance of allelic losses and CpG island methylation of p15(INK4b) gene inactivation and support a tumor suppressor role for p15(INK4b) in T-cell lymphomas independent of p16(INK4a).