TheMETGene Is a Common Integration Target in Avian Leukosis Virus Subgroup J-Induced Chicken Hemangiomas

Abstract

ABSTRACTAvian leukosis virus subgroup J (ALV-J) is a simple retrovirus that can cause hemangiomas and myeloid tumors in chickens and is currently a major economic problem in Asia. Here we characterize ALV-J strain PDRC-59831, a newly studied U.S. isolate of ALV-J. Five-day-old chicken embryos were infected with this virus, and the chickens developed myeloid leukosis and hemangiomas within 2 months after hatching. To investigate the mechanism of pathogenesis, we employed high-throughput sequencing to analyze proviral integration sites in these tumors. We found expanded clones with integrations in theMETgene in two of the five hemangiomas studied. This integration locus was not seen in previous work characterizing ALV-J-induced myeloid leukosis.METis a known proto-oncogene that acts through a diverse set of signaling pathways and is involved in many neoplasms. We show that tumors harboringMETintegrations exhibit strong overexpression ofMETmRNA.IMPORTANCEThese data suggest that ALV-J induces oncogenesis by insertional mutagenesis, and integrations in theMEToncogene can drive the overexpression ofMETand contribute to the development of hemangiomas.