Avian retroviral integration into the c-myb locus is casually associated with the development of lymphomas in the bursa of Farbricius of chickens; these arise with a shorter latency than bursal lymphomas caused by deregulation of c-myc. This study indicates that c-myb mutation in embryonic bursal precursors leads to an oligoclonal population of developing bursal follicles, showing a variable propensity to form a novel lesion, the neoplastic follicle (NF). About half of such bursas rapidly developed lymphomas. Detection of changes in gene expression, during the development of neoplasms, was carried out by cDNA microarray analysis. The transcriptional signature of lymphomas with mutant c-myb was more limited than, and only partially shared with, those of bursal lymphomas caused by Myc or Rel oncogenes. The c-myb-associated lymphomas frequently showed overexpression of c-myc and altered expression of other genes involved in cell cycle control and proliferation-related signal transduction. Oligoclonal, NF-containing bursas lacked detectable c-myc overexpression and demonstrated a pattern of gene expression distinct from that of normal bursa and partially shared with the short-latency lymphomas. This functional genomic analysis uncovered several different pathways of lymphomagenesis by oncogenic transcription factors acting in a B-cell lineage.
The avian leukosis virus ⌬LR-9 causes a high frequency of B-cell lymphomas within weeks after injection into 10-day-old chicken embryos. These lymphomas result from proviral integrations into the oncogene c-myb. In contrast, LR-9, which lacks the 42-nucleotide gag gene deletion of ⌬LR-9, does not cause a high frequency of c-myb-associated short-latency lymphomas. Although viral replication rates and spliced env mRNA levels were found to be similar for both viruses, ⌬LR-9 exhibited an increase in readthrough transcription compared to LR-9. The ⌬LR-9 deletion is located in the region of the gag gene corresponding to the matrix (MA) protein as well as in the negative regulator of splicing (NRS) element. To test whether disruption of the NRS or of the MA protein was responsible for inducing short-latency lymphomas, we generated viruses with NRS point mutations that maintained the wild-type Gag amino acid sequence. One of the mutant viruses induced an even higher incidence than ⌬LR-9 of short-latency lymphomas with viral integrations into c-myb. Thus, we propose that disruption of the NRS sequence promotes readthrough transcription and splicing to the downstream myb gene, causing overexpression of a slightly truncated Myb protein, which induces short-latency tumors.A defining characteristic of retroviruses is that they randomly integrate their reverse-transcribed genome into the genome of the host cell. Selection for a specific integration site can occur when a retrovirus integrates into a proto-oncogene, resulting in a clonal tumor. When an avian leukosis virus (ALV) is injected into 1-day-old chicks, it typically induces clonal B-cell lymphomas exhibiting proviral DNA integrated into the oncogene c-myc (13). These B-cell lymphomas result from the deregulated expression of c-myc and take several months to develop. However, if an ALV is injected into 10-to 12-day-old chicken embryos, approximately 14% of the hatched chickens develop short-latency B-cell lymphomas that cause death within weeks (29). Moreover, injection of chicken embryos with the recombinant ALV EU-8 (which has a 42-nucleotide [nt] deletion in the gag gene) leads to short-latency B-cell lymphomas in 40 to 80% of the chickens (16,32).Most of these short-latency lymphomas contain proviral DNA integrated into the first intron of c-myb (15, 29). Transcription initiates at the ALV promoter in the 5Ј long terminal repeat (LTR) and reads through the polyadenylation sequence in the 3Ј LTR to transcribe the downstream c-myb gene (see Fig. 1). Splicing then occurs from the 5Ј splice site in the 5Ј end of the viral gag gene to the 3Ј splice site of the c-myb second exon ( Fig. 1) (15). Translation of the ALV-myb hybrid RNA yields a Myb protein that is truncated at its N terminus by 20 amino acids (15). Truncated Myb, in contrast to full-length Myb, is highly oncogenic when expressed from retroviral vectors introduced into 12-day-old chicken embryos (15). Further, the transcriptional profile of the short-latency, c-myb-associated tumors is distinct from that of c...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.