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PATHOGENIC POTENTIAL OF MYELOBLASTOSIS ASSOCIATED VIRUS (MAV)

by Pr. Bernard PERBAL

MAV is a replication competent retrovirus that does not contain cell-derived oncogenic sequences. It induces predominantly nephroblastoma and osteopetrosis in chickens. The studies carried out in my laboratory have established that the avian nephroblastoma induced by MAV1(N) is a unique model of the pediatric Wilms' tumor. Our current objectives are to i) identify the target cells of MAV and cellular proteins involved in virus-host interactions, ii) evaluate the participation of MAV U3 sequences in the establishement and maintenance of the tumor state, and iii) characterize the insertion sites of proviral DNA in the genome of tumor cells.

Althought the current view is that the tumor cells arise at the earliest stages of kidney differentiation and develop along with normal elements of the kidney under the influence of inapropriate epigenic signals, the identity of the MAV target cells has not been established as yet. The in situ hybridization results that we have obtained suggest that in the hyperplastic tissue expanding upon MAV-infection, blastemal cells commited to epithelial differentiation are MAV targets and likely express transcription factors responsible for very efficient expression of MAV mRNAs in these cells.

Previous time course studies of renal lesions induced by different chimearic viruses established that the MAV U3LTR are both necessary and suffcient for the induction of nephroblastoma. Several studies have highlighted the role of the U3 region in conferring tumorigenicity on avian and murine retroviruses. The U3 region of MAVcontains several distinctive structural features which may be responsible for the unique pathogenic potential of MAV. We have constructed recombinant proviral MAV genomes deleted for one of the six MAV-specific U3 repeats. The role of these repeats with respect to the transcriptional activity of U3 has been assessed ex vivo and the ability of each recombinant virus to induce nephroblastoma has been analyzed in vivo. The results obtained highlight the critical role of these repeats on conferring to MAV its tumorigenic properties.

Screening of lambda libraries of tumor DNA allowed us to discover the nov, a nephroblastoma overexpressed, gene whose expression was found to be altered in all avian and human nephroblastomas studied to date. The nov gene encodes a putative negative regulator of cell growth whose activity is associated with polarized differentiation of kidney cells and other tissues such as striated muscle, cartilage, bone, and nervous system. The recent results that we have obtained provide an explanation for MAV inducing nephroblastomas. We have now cloned all 20 junction fragments from three independent tumors representing varous developmental tumor stages and used them as probes for screening BAC (Bacterial Artificial Chromosomes) and PAC (P1-derived Artificial Chromosomes) libraries. It will be interesting to establish whether other MAV targets are also involved in normal differentiation.