Induction of leukemia by both fractionated x-irradiation and radiation leukemia virus involves loci in the chromosome 2 segment H-30-A.

Abstract

A common link between the induction of leukemia by (i) fractionated doses of x-irradiation and (ii) radiation leukemia virus in mice may be established by the observation that the segment of chromosome 2. between the loci for the minor histocompatibility antigen H-30 and color coat agouti (H-30-A) includes distinct loci involved in susceptibility to leukemogenesis induced by factors i and ii.Kaplan and Brown (1) first showed that fractionated doses of xirradiation (FX) can cause leukemia in mice. Gross (2) and Lieberman and Kaplan (3) subsequently reported the transfer of neoplasia by radiation-induced leukemia virus (RadLV) obtained from radiation-induced leukemias. The extent to which the activation of such viruses plays a role in the etiology of the disease has become an important question (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). We report studies in mice from which comparisons can be made of genetic factors that influence susceptibility and resistance to leukemia induced by FX or by infection with an isolate of RadLV (the Kaplan strain of RadLV). MATERTIALS AND METHODSMice, virus, virus inoculation, leukemogenic FX, and antiserum used have been described (21,22).In the cell binding radioimmunoassay, antisera binding to cellular antigens. were measured by indirect radioimmunoassay with "2I-labeled protein A. Mice were bled retroocularly into heparinized tubes, yielding about 0.5 ml of blood, which was treated once with Tris/ammonium chloride to lyse the erythrocytes. The remaining lymphocytes (about 8 X 105) were added to four test tubes, two of which received 50 ,ul of a 1:20 dilution of antiserum against the lymphocyte antigen Ly-11.2, and the others received 50 ,ul of serum diluted 1:20 from unimmunized mice (NMS). Incubation was for 30 min. The cells were diluted with 1 ml of phosphate-buffered saline/fetal calf serum, centrifuged, and resuspended in 50 ,u1 of a 1:10 dilution (2.5 ,ug) of '"I-labeled protein A [specific activity, 1,920 Ci/ mmol (Amersham); 1 Ci = 3.7 X 1010 becquerels] to give 1.5 X 105 cpm per tube. After 30 min at room temperature, the cells were washed three times. The pellets were transferred to new tubes and assayed for radioactivity in a Beckman gamma counter 4000. RESULTS Involvement of Distinct Genes. Recombinant inbred (RI) lines of mice may be used to assess linkage of various genetic loci (23,24). Such RI strains are constructed by crossing two strains of mice and inbreeding F2 offspring to homozygosity (24). Loci that are linked tend to stay in the same initial parental combination (24), and this can be used to infer linkage relationships. We used the CXB/By series (23) of seven RI lines to map loci involved in susceptibility to FX-and RadLV-induced leukemia. These studies demonstrated that distinct genes are involved in susceptibility to leukemia induced by FX and RadLV. For example, some of the RI strains, such as CXBG were highly susceptible to the induction ofleukemia by FX but resistant to induction by RadLV, and some such as CXBD showed th...

Murine Ly-6 multigene family is located on chromosome 15.

“…The duplication of the distal portion of chromosome 15 was frequently associated with the occurrence of T-cell leukemias (36, 37). As mentioned above, the major locus influencing susceptibility to leukemia induction by fractionated irradiation, Ril-i, has been remapped to a position on chromosome 15, closely linked to the Ly-6 locus (27,38). As indicated in Fig.…”

Association of endogenous viral loci with genes encoding murine histocompatibility and lymphocyte differentiation antigens.

“…Other studies from our laboratory, primarily designed to map lymphocyte antigen-encoding loci, indicated that viral sequences are often found adjacent to histocompatibility loci and genes encoding several Ly (H/Ly) antigens (1,7,8), but these studies did not address the issue directly because serological reagents were used. The current report directly demonstrates that endogenous viral sequences are often found tightly linked to H/Ly loci and viral inducibility or susceptibility loci.…”

Effects of fractionated x-irradiation on the Ly-6--Ril-1--Pol-5 region

“…Assuming that the differences in susceptibility observed in the two congenic strain pairs are attributable to the same locus, Ril-1, these results support the conclusion that Ly-6, Ril-1, and H-30 are tightly linked. More recent work has determined that a retroviral integration site, Pol-5, is tightly linked to both the H-30 and Ly-6 loci (Meruelo et al 1983. We have utilized probes to follow the segregation of the Pol-5 locus in interspecies somatic cell hybrids, and the inheritance of an associated RFLP in mice.…”

“…M. B. Amari. riding influence in susceptibility to the disease. Previous work has demonstrated linkage between and Ril-1 (Meruelo et al 1983). Strain distribution pattern analyses with recombinant inbred (RI) strains and in situ hybridization techniques have placed the Ly-6--Ril-1--H-30 gene complex on chromosome 15 ).…”