Several polymorphic DNA restriction endonuclease fragments hybridizing with xenotropic and ecotropic envelope virus probes map adjacent to minor histocompatibility and lymphocyte (H/Ly) antigen-encoding loci. Viral DNA restriction fragments are associated with Ly-17 on chromosome 1, H-30, H-3, and H-13 on chromosome 2, Ly-21 on chromosome 7, H-28 on chromosome 3, and H-38 (chromosomal location as yet undetermined). In each case no recombinant can be found between the H/Ly locus in question and the virus-related restriction fragment, suggesting that linkage is very tight. Although some viral loci map to locations where no H/Ly has yet been mapped, the frequency and tightness of linkage in the seven instances described, coupled with the large number of as yet unmapped H/Ly loci, suggests that the associations found are significant.
The region of chromosome 2 between H-13 and H-3 has been shown to contain loci coding for a variety of other alloantigens, including Ly-4 and the locus coding for (82-microglobulin. Herein we show that and Ly-il are coded for by genes in a segment of chromosome 2 adjacent to the H-3-H-13 region and that this segment of chromosome also contains the tightly linked loci coding for antigens Ala-i, DAG, H9/25, H-30, Ly-8, and ThB. In addition, at least one locus (and probably more) affecting susceptibility to leukemia induction is found within this gene cluster.
Susceptibility to radiation-induced leukemia in (A/J x B10)F2 mice is encoded for by genes in chromosomes 1, 2, and 4. The loci involved in chromosomes 1 and 4 are close to or similar to xenotropic virus inducibility locus on chromosome 1 and a locus-affecting expression of xenotropic MuLV envelope-related cell surface antigens. Radiation-induced leukemia-1 (Ril-1) on chromosome 2 plays an overriding influence in susceptibility to the disease. This locus might encode ecotropic viral-associated genetic information or might contain cellular sequences with oncogenic potential. These findings are of interest in view of the importance of recombinant viruses to leukemogenesis. Furthermore, it is intriguing that Ril-1 is located in a chromosomal site rich in thymus differentiation-specific loci. An explanation for tissue-specific activation of endogenous viruses is that activation of the virus in question is dependent on differentiation-specific steps.
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...
A serum raised by immunizing (B10.A(4R) X B10.HTT)F1 mice against A.AL lymphocytes detects a new antigenic determinant designated Ly-22.2. Ly-22.2 expression is under the control of two independently segregating genes, one of which maps to chromosome 4 adjacent to a locus affecting XenCSA expression. Ly-22.2 is present in varying amounts in all lymphoid organs, but appears to be expressed primarily on T lymphocytes. Ly-22.2 is not detectable in brain, kidney, lung, liver, or erythrocytes. Strain distribution studies show Ly-22.2 is present in all strains examined except B10-derived congenic strains. It is of interest that C57BL/6 and C57BL/10 mice differ in the expression of this antigen.
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