INACTIVATIONS OF P16(INK4A)-ALPHA, P16(INK4A)-BETA AND P15(INK4B) GENES IN 2',3'-DIDEOXYCYTIDINE-INDUCED AND 1,3-BUTADIENE-INDUCED MURINE LYMPHOMAS

The p16(INK4a) (alpha and beta form) and p15(INK4b) genes were analyse d for homozygous deletion, hypermethylation and point mutation in B6C3 F1 mouse lymphomas induced by 2',3'-dideoxycytidine or 1,3-butadiene, Although the p16(INK4a)-alpha gene appeared normal in DNA from 2',3'-d ideoxycytidine-induced lymphomas, Southern analyses revealed homozygou s deletions or rearrangements of the p16(INK4a)-beta and/or p15(INK4b) genes in four of 16 tumours, Surprisingly, two of these lymphomas sho wed exclusive deletions of the p16(INK4a) EI beta exon, The p15(INK4b) promoter region was hypermethylated in two additional 2',3'-dideoxycy tidine-induced lymphomas, In contrast, homozygous deletions spanning t he p16(INK4a), and p15(INK4b) loci were observed in only two of 31 1,3 -butadiene-induced tumours, Thus, these cyclin dependent kinase inhibi tor genes may play a significant role in chemically induced mouse lymp homas and support the contention of tumour suppressor activity for the p19(ARF) protein encoded by the p16(INK4a)-beta gene, Different genet ic pathways may be involved in the development of these chemically ind uced tumours since we have previously shown that mutations in p53 and rns genes are common in 1,3-butadiene- but not 2',3'-dideoxycytidine-i nduced lymphomas,.