Efficiency Alleles of the Pctr1 Modifier Locus for Plasmacytoma Susceptibility

Abstract

The susceptibility of BALB/c mice to pristane-induced plasmacytomas is a complex genetic trait involving multiple loci, while DBA/2 and C57BL/6 strains are genetically resistant to the plasmacytomagenic effects of pristane. In this model system for human B-cell neoplasia, one of the BALB/c susceptibility and modifier loci, Pctr1, was mapped to a 5.7-centimorgan (cM) chromosomal region that includedCdkn2a, which encodes p16^INK4a and p19^ARF, and the coding sequences for the BALB/c p16^INK4a and p19^ARF alleles were found to be polymorphic with respect to their resistant Pctr1counterparts in DBA/2 and C57BL/6 mice (45). In the present study, alleles of Pctr1, Cdkn2a, andD4Mit15 from a resistant strain (BALB/cDAG) carrying DBA/2 chromatin were introgressively backcrossed to the susceptible BALB/c strain. The resultant C.DAG-Pctr1 Cdkn2a D4Mit15 congenic was more resistant to plasmacytomagenesis than BALB/c, thus narrowingPctr1 to a 1.5-cM interval. Concomitantly, resistant C57BL/6 mice, from which both gene products of the Cdkn2agene have been eliminated, developed pristane-induced plasma cell tumors over a shorter latency period than the traditionally susceptible BALB/cAn strain. 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 the two p19^ARF alleles displayed similar potencies in both assays. We propose that the BALB/c susceptibility/modifier locus, Pctr1, is an “efficiency” allele of the p16^INK4a gene.

ACKNOWLEDGMENTS

We acknowledge Richard Nordan, who passed away during the course of these studies, and his colleague Cindy Thompson for providing us with IL-6 and valuable advice concerning transfections of plasmacytoma cells. We thank Wei Jiang for providing us with the EGFPF vector for use in our transfections and Han-Woong Lee for advice on breeding the p16 knockout mice. In addition, we thank Douglas Lowy for his insightful editorial comments and Xiaolan Qian for her involvement in the ras transformation assays.