Genetic determinants of feline leukemia virus-induced lymphoid tumors: patterns of proviral insertion and gene rearrangement

Abstract

The genetic basis of feline leukemia virus (FeLV)-induced lymphoma was investigated in a series of 63 lymphoid tumors and tumor cell lines of presumptive T-cell origin. These were examined for virus-induced rearrangements of the c-myc,flvi-2 (bmi-1),fit-1, and pim-1 loci, for T-cell receptor (TCR) gene rearrangements, and for the presence of env recombinant FeLV (FeLV-B). The myc locus was most frequently affected in naturally occurring lymphomas (32%; n = 38) either by transduction (21%) or by proviral insertion (11%). Proviral insertions were also common atflvi-2 (24%). The two other loci were occupied in a smaller number of the naturally occurring tumors (fit-i, 8%; pim-i, 5%). Examination of the entire set of tumors showed that significant numbers were affected at two (19%Yo) or three (5%) of the loci. Occupation of the fit-i locus was observed most frequently in tumors induced by FeLV-myc strains, whileflvi-2 insertions occurred with similar frequency in the presence or absence of obvious c-myc activation. These results suggest a hierarchy of mutational events in the genesis of feline T-cell lymphomas by FeLV and implicate insertion atfit-i as a late progression step. The strongest links observed were with T-cell development, as monitored by rearrangement status of the TCR n-chain gene, which was positively associated with activation of myc (P < 0.001), and with proviral insertion at flvi-2 (P = 0.02). This analysis also revealed a genetically distinct subset of thymic lymphomas with unrearranged TCR ,8-chain genes in which the known target loci were involved very infrequently. The presence of env recombinant FeLV (FeLV-B) showed a negative correlation with proviral insertion at fit-i, possibly due to the rapid onset of these tumors. These results shed further light on the multistep process of FeLV leukemogenesis and the relationships between lymphoid cell maturation and susceptibility to FeLV transformation.

Clinical aspects of feline immunodeficiency and feline leukemia virus infection

“…When they enter a new cell, these recombinant viruses are oncogenic. In a study of 119 cats with lymphomas, transduction or insertion of the myc locus had occurred in 38 cats (32%) (Tsatsanis et al, 1994). Thus, FeLV-induced neoplasms are caused, at least in part, by somatically acquired insertional mutagenesis in which the integrated provirus may activate a proto-oncogene or disrupt a tumor suppressor gene.…”

High prevalence of non-productive FeLV infection in necropsied cats and significant association with pathological findings

“…The envelope protein p15E has been shown to have immunosuppressive effects Mathes et al, 1978). Insertional mutagenesis induced by integration of the provirus into the cell genome seems to be associated with tumor development (Levy et al, 1997;Tsatsanis et al, 1994;Levy and Lobelle-Rich, 1992;Levy et al, 1984;Neil et al, 1984).…”

Use of nested polymerase chain reaction (PCR) for detection of retroviruses from formalin‐fixed, paraffin‐embedded uveal melanomas in cats

“…In a study of feline lymphomas, transduction or insertion of the myc locus occurred in 32% of 119 tumors. 38 Accordingly, it may be possible that during infection with FeLV anterior uveal cells become latently infected, with viral persistence for long periods of time, perhaps years. At some point, cellular transformation of melanocytes into malignant melanoma cells may occur, resulting in the clinical appearance of ocular neoplasia.…”