| Retroviruses integrate their reverse transcribed genome into that of the host cell. This can lead to the inadvertent activation of a host proto-oncogene. When the avian leukosis virus (ALV) ΔLR-9 is injected into 10 day-old chick embryos, B-cell lymphomas develop due to integration into, and activation of, c-myb. These tumors develop rapidly, and the chickens die within a short-latency period (10 weeks or less after hatching). On the other hand, injection of the ALV LR-9 does not lead to a high frequency of short-latency lymphomas.; ΔLR-9 differs from LR-9 by a 42-nucleotide deletion in the viral gag gene. We showed that ΔLR-9 is able to cause a high frequency of short-latency lymphomas because the deletion disrupts the RNA element named the negative regulator of splicing (NRS) and not because of the in-frame deletion of 14 amino acids of the viral matrix protein. We then characterized the viral integrations into c-myb that led to B-cell lymphomas. We also showed that c-myb-induced B-cell lymphomas have a distinct transcriptional profile compared to B-cell lymphomas due to c-myc activation.; The deletion in the ΔLR-9 virus is in the 5′ region of the 230 nucleotide-long NRS sequence. We showed that the deletion reduced the binding of the cellular splicing factor ASF/SF2 and of hnRNP H, and that both 5′ and 3′ NRS regions (the latter binds U1 snRNP) are necessary for proper NRS activity. At a functional level, we showed that the NRS promotes the proper polyadenylation of viral transcripts and thus limits readthrough transcription into adjacent cellular genes like c-myb. However, the NRS is not important for limiting splicing to the viral gene env, and NRS mutations seem to have no large effects on ALV replication. Nevertheless, the NRS might limit splicing to cellular genes after readthrough transcription, analogous to its effect of limiting splicing to the viral gene src in Rous sarcoma virus. Thus, ΔLR-9 seems to cause a high frequency of short-latency lymphomas because the partial deletion of the NRS leads to an increase in readthrough transcription and splicing to the cellular oncogene c-myb . |
