Efficiency alleles of the Pctr1 modifier locus for plasmacytoma susceptibility

The susceptibility of BALB/c mice to pristane-induced plasmacytomas is a co mplex genetic trait involving multiple loci, while DBA/2 and C57BL/6 strain s are genetically resistant to the plasmacytomagenic effects of pristane. I n this model system for human B-cell neoplasia, one of the BALB/c susceptib ility and modifier loci, Pctr1, was mapped to a 5.7-centimorgan (cM) chromo somal region that included Cdkn2a, which encodes p16(INK4a) and p19(ARF), a nd the coding sequences for the BALB/c p16(INK4a) and p19(ARF) alleles were found to be polymorphic with respect to their resistant Pctr1 counterparts in DBA/2 and C57BL/6 mice (45), In the present study, alleles of Pctr1, Cd kn2a, and D4Mit15 from a resistant strain (BALB/cDAG) carrying DBA/2 chroma tin were introgressively backcrossed to the susceptible BALB/c strain. The resultant C.DAG-Pctr1 Cdkn2a D4Mit15 congenic was more resistant to plasmac ytomagenesis than BALB/c, thus narrowing Pctr1 to a 1.5-cM interval, Concom itantly, resistant C57BL/6 mice, from which both gene products of the Cdkn2 a gene have been eliminated, developed pristane-induced plasma cell tumors over a shorter latency period than the traditionally susceptible BALB/cAn s train. Biological assays of the p16(INK4a) and p19(ARF) alleles from BALB/c and DBA/2 indicated that the BALB/c p16(INK4a) allele was less active than its DBA/2 counterpart in inducing growth arrest of mouse plasmacytoma cell lines and preventing ras-induced transformation of NIH 3T3 cells, while th e two p19(ARF) alleles displayed similar potencies in both assays. We propo se that the BALB/c susceptibility/modifier locus, Pctr1, is an "efficiency" allele of the p16(INK4a) gene.