Tumor spectrum in ARF-deficient mice

The p19(ARF) product Of the INK4a/ARF locus is induced in response to poten tially oncogenic hyperproliferative signals and activates p53 by interferin g with its negative regulator, Mdm2, Mice lacking ARF are highly prone to t umor development, and in this study, 80% of these animals spontaneously dev eloped tumors and died within their first year of life, Mice that were hete rozygous for ARF also developed tumors after a longer latency, whereas thei r wild-type littermates did not. In heterozygotes, tumor formation was acco mpanied by loss of the residual ARF allele and/or lack of ARF mRNA expressi on, implying that ARF can act as a canonical "two-hit" tumor suppressor gen e, Tumors occurred earlier in life in ARF-null animals that were neonatally irradiated or given dimethylbenzanthrene, and several animals treated with carcinogen simultaneously developed multiple forms of malignancy arising f rom distinct cell lineages, Although p53-null mice primarily develop lympho mas and fibrosarcomas, the frequency of these two tumor types was inverted in ARF-null animals, with undifferentiated sarcomas predominating in a 3:2 ratio; 28% of ARF-null animals developed carcinomas and tumors of the nervo us system, which have been rarely observed in untreated p53-null mice, The longer latency of tumor formation in ARF-null versus p53-null mice, therefo re, appears to enable a broader spectrum of tumors to emerge.