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Identification of two genes on chromosome 4 that determine resistance to plasmacytoma induction in mice
M Potter1, E B Mushinski, J S Wax
1Laboratory of Genetics, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Abstract:
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 resistant phenotype of DBA/2, BALB/c.DBA/2 (C.D2) congenic strains were constructed, and the susceptibility and resistance to PCT development were determined. PCT formation takes place over an extended period of 365 days but begins morphologically in focal proliferations of atypical plasma cells (foci) in the reactive oil granuloma that forms on mesenteric surfaces. Cells from some of these foci spread to other locations in oil granuloma tissue, forming new foci. Mice that develop six or more foci appear to be progressing towards eventual overgrowth and replacement 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 foci, whereas less than 5% of resistant DBA/2, BALB/c x DBA/2 F1 (hereafter called CD2F1), C57BL/6, and BALB/cJ mice had 6 or more foci. Four CD2 congenic strains carrying D2 alleles of genes on chromosomes other than chromosome 4 were highly susceptible. Between 0 and 20% of the mice in C.D2-Chr 4 congenic strains C.D2-MIA, C.D2-TF3, C.D2-Fv-1n/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-1n/n and C.D2-Pnd7 were discontinuous with those in C.D2-TF3, C.D2-Lgm-1A, C.D2-Lgm-1B, C.D2-Lgm-1C, and C.D2-Lgm-1H, indicating there are at least two genes (Pctr1 and Pctr2) in the distal half of this chromosome that confer resistance. Pctr1 is located between Ifa and D4Rck41, and Pctr2 is between Tnfr-1 and Pkcz. Each locus acting alone distinctly conferred a partial resistant phenotype. Pctr1 and Pctr2 did not appear to prevent the formation of clonal foci but did appear to limit the ability of the plasma cells in foci to acquire greater autonomy; thus, these genes affect tumor progression.
Insights
Genetic analysis reveals two key genes, Pctr1 and Pctr2, on chromosome 4 confer resistance to plasmacytoma development in mice. These genes limit tumor progression rather than initial formation.
Area of Science:
- Immunology
- Genetics
- Oncology
Background:
- BALB/cAn mice are highly susceptible to plasmacytoma (PCT) induction by paraffin oil, while DBA/2 mice are resistant.
- PCTs develop from atypical plasma cell foci within oil granulomas on mesenteric surfaces.
- Tumor progression is indicated by the development of six or more foci.
Purpose of the Study:
- To identify genes responsible for the dominant resistance to plasmacytoma development in DBA/2 mice.
- To investigate the genetic control of the resistant phenotype using congenic mouse strains.
Main Methods:
- Construction and analysis of BALB/c.DBA/2 (C.D2) congenic strains.
- Assessment of susceptibility and resistance to PCT development over 365 days.
- Mapping of resistance genes to specific chromosomal locations.
Main Results:
- Congenic strains with DBA/2 alleles on chromosomes other than chromosome 4 remained susceptible.
- Congenic strains carrying DBA/2 segments on chromosome 4 exhibited resistance.
- At least two resistance genes, Pctr1 and Pctr2, were localized to the distal half of chromosome 4.
- Pctr1 and Pctr2 conferred a partial resistant phenotype, limiting tumor progression but not initial focus formation.
Conclusions:
- The resistance to plasmacytoma development in DBA/2 mice is controlled by at least two genes on chromosome 4.
- Pctr1 and Pctr2 influence the autonomy of plasma cell foci, thereby affecting tumor progression.
- These findings provide insights into the genetic mechanisms underlying plasmacytoma development and resistance.