RAV-1 insertional mutagenesis: disruption of the c-myb locus and development of avian B-cell lymphomas

Abstract

Infection of young chickens with RAV-1, a subgroup A isolate of avian leukosis virus, results in the development of lymphoid leukosis, a B-cell lymphoma characterized by provirus insertion into the c-myc locus. We report here that when 12to 13-day-old embryos rather than 1-day-old chickens were infected with RAV-1, a novel B-cell lymphoma developed in which proviral insertions had activated expression of the c-myb gene. These tumors expressed elevated levels of a 4.5-kilobase myb-containing mRNA transcript that contained c-myb sequences not found in v-myb. The c-myc locus in these tumors appeared normal. The biological properties of the activated myb lymphoma were distinct from those of lymphoid leukosis. Metastatic disease developed within 7 weeks of infection. Distinct intermediate pathogenic stages with preneoplastic and primary neoplastic lesions were not detected. Although bursal tissues appeared to be nonmalignant on gross examination, Southern analyses of bursal DNA revealed the presence of tumor with the same clonal origin as abdominal lymphoma masses. The dependence on embryonic infection for development of activated myb lymphoma suggests that the target cells in which c-myb is activated are found only in embryos and are distinct from those cells that give rise to lymphoid leukosis.

Characterization of the sequence-specific interaction of mouse c-myb protein with DNA.

“…Truncation of RI-coding sequences in retrovirus-mediated myeloid tumours may remove such constraints. In this regard, it is interesting to note that insertional activation of c-myb in avian B cell lymphomas (as opposed to myeloid tumours) appears to be associated with expression of novel proteins in which the amino-terminal truncation is far less extensive (Kanter et al, 1988;Pizer and Humphries, 1989) and in which the entire reiterated DNA-binding region would remain intact. Thus, it is conceivable that these two modes of activation in tumours of distinct haemopoietic lineages reflect requirements for binding to different spectra of target sites in these cells, with specificity perhaps endued by the presence or absence of Ri in the mutated proteins.…”

“…The c-myb gene has been implicated in the induction of a number of haemopoietic malignancies in experimental animals. For example, transduction of c-myb sequences by the avian retroviruses AMV and E26 was associated with leukaemias of immature myeloid phenotype (Bishop and Varmus, 1985), while insertion of retroviruses into this locus has been observed in certain murine myeloid leukaemias (Mushinski et al, 1983;Weinstein et al, 1986) and avian B cell lymphomas (Kanter et al, 1988;Pizer and Humphries, 1989). Typically, these induction events involved disruption of c-myb coding sequences, resulting in expression of truncated analogues of the 75 000 mol.…”

“…wt protein comprising six amino acids specified by the retrovirus gag gene fused Oxford University Press to c-myb sequences truncated at both the amino and carboxy termini (Klempnauer et al, 1983). In some contrast, retrovirus insertion appears to result in expression of genes that encode proteins singly truncated at either the amino or carboxy termini Shen-Ong et al, 1986;Kanter et al, 1988;Pizer and Humphries, 1989).…”

Reticuloendotheliosis virus REV-T(REV-A)-induced neoplasia: development of tumors within the T-lymphoid and myeloid lineages

“…Probes to identify v-rel, CLl.-Cp.2, and CX have already been described (3). Endogenous c-myc and c-myb RNAs were identified by Northern analysis by using a 1-kb exon 3-specific fragment isolated from c-myc and an EcoRI-SalIspecific 400-bp myb fragment derived from pVM2, respectively (23).…”

Infrequent involvement of c-fos in avian leukosis virus-induced nephroblastoma

“…Avian leukosis viruses (ALVs) can cause cancer when proviral insertions convert a proto-oncogene to an oncogene or when proto-oncogene sequences are incorporated into the viral genome. ALV-induced B-cell lymphomas are associated with proviral insertions into c-myc or c-myb (7,8,10,13,14,17), whereas cases of erythroblastosis are associated with insertions into c-erbB (6,11,15). An occasional lymphoma is associated with the incorporation of c-myc sequences into a viral genome (17).…”