2 DOMINANT HOST-RESISTANCE GENES TO PRE-B LYMPHOMA IN WILD-DERIVED INBRED MOUSE STRAIN MSM MS/

To explore possible host genes suppressing spontaneous B-lymphomagenes is in the mouse, expression of ecotropic murine leukemia virus (E-MuLV ) and lymphoma development were observed in crosses between the pre-B lymphoma-prone SL/Kh and low-lymphoma strains of mice. E-MuLV expressi on was intensely inhibited in F-1 hybrids with the strains either with the Fv-1(b) allele (BALB/c, C57BL/10, and A/J) or with the Fv-1(nr) a llele (NZB). In these F-1 mice, no lymphoma developed by 18 months of age. On the other hand, F-1 hybrids with the strains with the Fv-1(n) allele [C3H/He, CBA/N, SJL, DBA/2, and MSM/Ms (hereafter referred to a s MSM)], high or intermediate levels of E-MuLV expression sere observe d. Lymphoma incidence in these F-1 hybrids, however, was low. This obs ervation suggests the presence of non-Fv-1 dominant resistance genes i n these strains. In an attempt to characterize such host genes, we ana lyzed crosses between SL/Kh mice and a wild mouse-derived inbred strai n, MSM/Ms. The latter was susceptible to N-tropic virus expression, bu t (SL/Kh x MSM)F-1 hybrids did not develop any lymphomas. Of 60 SL/Kh x (SL/Kh x MSM)F-1 hybrids, 14 B-lineage lymphomas, including 13 pre-B and 1 follicular center cell lymphoma, developed by 18 months of age. This was compatible with the hypothesis of two independently segregat ing dominant genes of MSM suppressing lymphomagenesis. By scanning all chromosomes for linkage of lymphoma susceptibility with polymorphic m icrosatellite loci, one significant linkage disequilibrium was found i n the proximal segment of chromosome 17, containing D17MIT44 (map posi tion 15.0) to D17MIT150 (position 33.3), and another linkage disequili brium, in the midproximal segment of chromosome 18, containing D18MIT9 0 (map position 28.0) and D18MIT140 (37.0). All 13 pre-B lymphoma-bear ing backcross mice were homozygous for SL/Kh-derived alleles at these loci. We named the gene on chromosome 17 Msmr1 (for MSM resistance 1) and that on chromosome 18 Msmr2 (for MSM resistance 2).