IDENTIFICATION OF 2 GENES ON CHROMOSOME-4 THAT DETERMINE RESISTANCE TO PLASMACYTOMA INDUCTION IN MICE

BALB/cAn mice are highly susceptible to the induction of plasmacytomas (PCTs) by the i.p. injection of paraffin oils, whereas DBA/2 mice are solidly resistant. To search for genes that control the dominant resi stant phenotype of DBA/2, BALB/c.DBA/2 (C.D2) congenic strains were co nstructed, and the susceptibility and resistance to PCT development we re determined. PCT formation takes place over an extended period of 36 5 days but begins morphologically in focal proliferations of atypical plasma cells (foci) in the reactive oil granuloma that forms on mesent eric surfaces. Cells from some of these foci spread to other locations in oil granuloma tissue, forming new foci. Mice that develop six or m ore foci appear to be progressing towards eventual overgrowth and repl acement of all peritoneal tissues with PCT cells. From Days 100 to 250 , between 28 and 56% of PCT-susceptible BALB/cAn mice had 6 or more fo ci, whereas less than 5% of resistant DBA/2, BALB/c x DBA/2 F-1 (herea fter called CD2F(1)), C57BL/6, and BALB/cJ mice had 6 or more foci. Fo ur C.D2 congenic strains carrying D2 alleles of genes on chromosomes o ther than chromosome 4 were highly susceptible. Between 0 and 20% of t he mice in C.D2-Chr 4 congenic strains C.D2-MIA, C.D2-TF3, C.D2-Fv-1(n /n), C.D2-Pnd7, C.D2-Lgm-1A, C.D2-Lgm-1B, C.D2-Lgm-1C, and C.D2-Lgm-1H developed 6 or more foci from 125 to 260 days, indicating resistance. The segments of DBA/2 chromosome 4 chromatin in C.D2-FV-1(n/n) and C. D2-Pnd7 were discontinuous with those in C.D2-TF3, C.D2-Lgm-1A, C.D2-L gm-1B, C.D2-Lgm-1C, and C.D2-Lgm-1H, indicating there are at least two genes (Pct(r1) and Pct(r2)) in the distal half of this chromosome tha t confer resistance. Pct(r1) is located between Ifa and D4Rck41, and P ct(r2) is between Tnfr-1 and Pkcz. Each locus acting alone distinctly conferred a partial resistant phenotype. Pct(r1) and Pct(r2) did not a ppear to prevent the formation of clonal foci but did appear to limit the ability of the plasma cells in foci to acquire greater autonomy; t hus, these genes affect tumor progression.