Murine plasmacytomagenesis : an experimental model of B-cell neoplasia

A chromosomal translocation which results in the illegitimate activation of the c-myc proto-oncogene by one of the three immunoglobulin (Ig) loci is invariably associated with human Burkitt's Lymphoma (BL), mouse plasmacytoma (MPC) and rat immunocytomas (RIC). In the MPC system a genetic predisposition linked to the BALB/c strain has been suggested. The precursor cell, site of origin and mechanism of the Ig/myc translocation have been unclear. We set up new experimental models to analyze this question and to study functional aspects of genetic resistance vs susceptibility. Donor derived MPC were induced in syngeneic BALB/c radiochimeras (RCh) repopulated either with fetal liver- (FL), bone marrow- (BM) or spleen-derived hematopoietic cells, after pristane + Abelson virus (A-MuLV) treatment, but less frequently after pristane alone, probably due to an underdeveloped oil granuloma (OG) observed in this group. Together with our early transfer experiments with conventional BALB/c mice, our present results do not support the idea that the gut IgA producing B-lymphocytes are the exclusive source of pre-MPC cells. The possibility that A-MuLV infected pretumoral cells can overcome the postulated OG deficiency was tested by transferring spleen cells from symptom-free E,u-mvc transgenic donors, infected in vitro with A-MuLV, into pristane pretreated and untreated syngeneic recipients. Translocation-free plasmacytomas were obtained mainly in pristane pretreated mice. It was concluded that A-MuLV infection of pristane pretreated BALB/c mice favours the survival and expansion of preneoplastic cells that carry an activated myc-gene. In order to asses whether part of the exceptional susceptibility of BALB/c would be determined at the level of the preneoplastic target cell, we have induced MPCs in reciprocal non-RCh between susceptible BALB/c and resistant DBA/2 mice (BALB/c~DBA/2). We found that 100% of the tumors originated from BALB/c cells in both reciprocal chimeras and concluded that at least part of the difference in the susceptibility of BALB/c and DBA/2 mice is determined at the level of the precursor cell itself. We further investigated whether the chromosomes involved in the Ig/myc translocations, the myc-carrying No 15, the /gH-carrying No 12, the IgK-carrying No 6, carry determinants that affect MPC susceptibility. We have exchanged the BALB/c chromosomes with homologues from resistant strains. This did not affect MPC susceptibility. We also showed that the translocations could be of uni- or biparental origm. We have selected a highly MPC susceptible subline (BALB/cM2/22) from the relatively resistant BALB/cJ strain. This line developes 62% MPCs after pristane oil induction and 52% after pristane followed by Abelson virus, compared to 11% and 0% respectively, in the original strain. Moreover, BALB/cM2/22 line shows a tendency to develop spontaneous plasmacytomas in untreated females. Five out of 6 spontaneous MPC have been exammed. All but one carried IgH/myc translocations. The exceptional tumor had a T(1;10)(G;CI) translocation and an interstitial duplication of segment (C1/E3) on one chromosome 5. This shows that a postulated chromosome damage by the MPC inducers such as pristane or silicon gel is not required to generate Ig/myc translocations in BALB/c mice. In contrast to Burkitt Iymphomas where both K/myc and lambda/myc translocations have been identified, the Ig light chain/myc translocations in pristane induced MPCs were all K/myc (6;15). We could detect the "missing" T(15;16) translocation repeatedly in MPCs mduced by pristane +A-MuLV. They contained juxtaposed myc and lambda genes as expected. One MPC that did not carry any of the three Ig/c-myc translocations contained a previously unknown T(6;12)(CI;B) translocation and expressed N-myc instead of c-myc. We showed that the translocation juxtaposed IgK and N-myc. This shows the functional equivalence of the two myc family genes in this system and indicates, moreover, that the translocation may have been generated at the pre- or pro-B-cell stage when N-myc is still transcriptionally active. This would imply, in line with other evidence, that the Ig/myc translocation does not interfere with further differentiation into a mature plasma cell