We have investigated the phenotypic changes that take place during the process of neoplastic transformation in the thymocytes of C57BL/Ka mice infected by the radiation leukemia virus (RadLV). By the combined use of antibodies against the envelope glycoprotein gp7O of RadLV, the transformation-associated cell surface marker lC1l, and the CD3-T-cell receptor (TCR) complex, we found that in the RadLV-infected thymus, the earliest expression of viral gp7O is in lCllhi cells; a small but significant percentage of these cells also express CD3. A first wave of viral replication, manifested by the expression of high levels of gp7O in thymocytes (over 70% positive), reaches a peak at 2 weeks; during this period, no significant changes are observed in the expression of IC11 or CD3. The population of gp70+ cells is drastically reduced at 3 to 4 weeks after infection. However, a second cohort of gp70+ cells appears after 4 weeks, and these cells express high levels of lCll and TCR determinants as well. RadLV-induced lymphomas differ from normal thymocytes in their CD4 CD8 phenotype, with domination by one or more subsets. Characterization of TCR gene rearrangements in RadLV-induced lymphomas shows that most of these tumors are clonal or oligoclonal with respect to the JP2 TCR gene, while the Jjll TCR gene is rearranged in a minority (4 of 11) of lymphomas. TCR VP repertoire analysis of 12 tumors reveals that 6 (50%o) express exclusively the V,I6 gene product, 2 (17%) are V05', and 1 (8%) each are VP8+ and VP9+. In normal C57BL/Ka mice, VPI6 is expressed on 12%, VII5 is expressed on 9%, V,B8 is expressed on 22%, and Vj89 is expressed on 4% of TCRhi thymocytes. Thus, it appears that RadLV-induced thymic lymphomas are not randomly selected with respect to expressed TCR VP type. Exposure to ionizing radiation is known to induce lymphoid malignancy in humans; the incidence of acute lymphoblastic leukemia in particular has been shown to correlate with radiation dose (34). To facilitate investigation of the basic mechanisms by which radiation induces leukemia, Kaplan and colleagues developed a murine model (21, 22) which they used to define the parameters for T-cell transformation. Wholebody irradiation, administered in fractionated doses, was found to induce a high incidence (>90%) of thymus-dependent lymphomas in C57BL/Ka mice (22). A thymotropic and lymphomagenic retrovirus, the radiation leukemia virus (RadLV), was recovered from cell extracts of some of these lymphomas (29, 30). After serial in vivo passage, RadLV-induced thymic lymphomas were found to be similar in frequency, clinical aspects, and latency to those produced by radiation. Several lymphoma cell lines from RadLV-induced tumors were established in culture (27); one such cell line, BLNVL3, was used to
mAb 1C11 was raised against the cells of retrovirus-negative, radiation-induced thymomas of C57BL/Ka mice. MAb 1C11 binds to radiation- and RadLV-induced C57BL/Ka lymphomas, to lymphomas of other mouse strains and to B-lineage tumors. The 1C11 Ag is expressed on a subpopulation of normal thymocytes that is enriched in immature cells. After fractionated x-irradiation, this percentage increases gradually during the preleukemic period, hence mAb 1C11 appears to identify a transformation-related cell surface molecule. This conclusion is supported by experiments demonstrating that flow microfluorimetry-sorted, 1C11-expressing preleukemic thymocytes progress rapidly to full neoplasia following intrathymic injection, whereas nonexpressing cells do not. Most of day-14 fetal thymocytes are as strongly positive as thymic lymphomas for the 1C11 Ag whereas Ag-activated T cell lines express moderate levels. Multiparameter flow microfluorimetry analysis shows that 1C11 is expressed predominantly on CD3-/lo thymic blast cells of three phenotypically defined subsets: CD4-8-, CD4-8+, and CD4+8+, all of which contain thymic progenitors. By immunohistochemical staining, the Ag is also found in association with epithelial cells on a variety of normal, nonlymphoid tissue, but is not detectable on heart tissue. The 1C11 antibody immunoprecipitates a disulfide-linked heterodimeric protein of 85/37 kDa and the antigenic determinant is located on the H chain of the molecule. When analyzed by SDS-PAGE under nonreducing conditions, the molecule exists as a 130-kDa protein. Enzymatic digestion of the heterodimer indicates that the H chain, but not the L chain, has at least three N-linked glycosylation sites. We propose that this novel cell surface glycoprotein may be associated with processes of differentiation and lymphomagenesis.
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