Feline leukemia virus integration atflvi-1 in naturally occurring lymphomas
Description
A locus in feline DNA, termed flvi-1, which may play an important role in the natural induction of lymphomas by feline leukemia virus (FeLV) was identified. Examination of a bank of 21 naturally occurring FeLV-positive feline lymphomas revealed that FeLV proviral integration occurs at flvi-1 in four independent tumors (19%). A portion of flvi-1 was determined to be evolutionarily conserved and allowed it to be mapped to mouse chromosome 2, in the proximal portion of band E. Independent proviral integrations occurred within a 2.4, kilobase region of flvi-1. Proviruses integrated at flvi-1 are exogenously acquired and are oriented in the same transcriptional direction with respect to the locus. Molecularly cloned flvi-1 did not hybridize with probes representing several previously described proviral integration domains or with probes representing several oncogenes. The natural feline lymphomas examined in this study were heterogeneous with respect to tissue of origin, cell type, and number of monoclonal proviral integrations. The four tumors in which flvi-1 is interrupted were classified as members of a phenotypic subgroup containing seven lymphomas, i.e., at least four (57%) of seven lymphomas of this type contained FeLV proviral integration at flvi-1 with the remaining three demonstrating tumor-specific flvi-1 alterations. Members of this phenotypic subgroup are non-T-cell lymphomas isolated from the spleen and contain an average of three proviruses, compared with an average of eight among all of the tumors examined. The small number of proviral integrations in tumors of this subgroup suggests that integration at flvi-1 may represent an early and significant event in the process of neoplastic transformation, possibly by abrogating the need for several additional contributing events. Sequence analysis revealed LTRs of molecularly cloned proviruses integrated at flvi-1 to exhibit a unique tandem triplication of a 21 bp sequence located 3$\sp\prime$ of the viral enhancer and 5$\sp\prime$ of the exogenous-specific HincII site. Gel retardation assays using a DNA fragment containing the triplication as probe revealed a specific novel DNA binding protein, termed FLV-2, in nuclear extracts of both EL4 T-cells and CS 19-10S erythroleukemia cells. (Abstract shortened with permission of author.)