F-mulv acceleration of myelomonocytic tumorigenesis in SV40 large T antigen transgenic mice is accompanied by retroviral insertion at Fli1 and a novel locus, Fim4

• Published in: Leukemia Vol. 16; no. 9; pp. 1827 - 1834
• Main Authors: KONE, J, ARROYO, J, HU, P, PRESCOTT, A, WU, H, YANG, L, ROE, B, PERKINS, A. S, SAVINELLI, T, LIN, S, BOYD, K, WU, Y, NIMMAKAYALU, M, COPELAND, N. G, JENKINS, N. A, QUMSIYEH, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01-09-2002; Nature Publishing Group
• Subjects: Abdomen; Acute myeloid leukemia; Animal tumors. Experimental tumors; Animals; Antigen T (large); Antigens; Antigens, Polyomavirus Transforming - genetics; Antigens, Polyomavirus Transforming - metabolism; Biological and medical sciences; Blotting, Southern; Cell cycle; Chromosome 6; Chromosome 7; Chromosome Mapping; Chromosomes, Artificial, Bacterial; Cloning, Molecular; Cooperation; Deoxyribonucleic acid; DNA; DNA Primers - chemistry; DNA-Binding Proteins - genetics; Early region; Experimental malignant blood diseases; Friend murine leukemia virus; Friend murine leukemia virus - genetics; Genes; Homology; Humans; In Situ Hybridization, Fluorescence; Insertion; Latency; Leukemia; Leukemia, Experimental - genetics; Leukemia, Experimental - metabolism; Leukemia, Experimental - virology; Leukemia, Myelomonocytic, Acute - genetics; Leukemia, Myelomonocytic, Acute - metabolism; Leukemia, Myelomonocytic, Acute - virology; Loci; Medical sciences; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Morbidity; Myelodysplastic syndrome; Myelodysplastic syndromes; Neoplasms; Polymerase Chain Reaction; Proto-Oncogene Protein c-fli-1; Proto-Oncogene Proteins; Proviruses - genetics; Retroviridae Infections - genetics; Retroviridae Infections - virology; Sarcoma; Simian virus 40; Synteny; Trans-Activators - genetics; Transgenic animals; Transgenic mice; Tumor Virus Infections - genetics; Tumor Virus Infections - metabolism; Tumor Virus Infections - virology; Tumorigenesis; Tumors; Virus Integration; Viruses; United States > US; Histiocytic lymphoma; Transgenic animal; Papovaviridae; Lymphoproliferative syndrome; Friend murine leukemia virus; Genetics; Large T antigen; Integration; Acute; Polyomavirus; Rodentia; Retroviridae; Chromosome 6; Malignant hemopathy; Tumorigenicity; Non Hodgkin lymphoma; Simian virus 40; Provirus; Infection; Virus; Mammalian type C retrovirus; Vertebrata; Mammalia; Mouse; C-Onc gene; Viral disease; Acute myelocytic leukemia
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2402598

We describe here the development of a murine system for the identification of genes involved in myelomonocytic neoplasms. Transgenic C57BL/6J mice expressing SV40 early region under a myelomonocytic promoter develop histiocytic sarcomas with a latency of 167 days. We used retroviral proviral tagging to accelerate tumorigenesis and to uncover genetic changes that contribute to tumor development. Infection of transgenic mice with Friend murine leukemia virus (F-MuLV) shortened the latency of morbidity to 103 days (P< 0.001); this was associated with clonal proviral integrations in tumor DNA. As expected for F-MuLV, proviral insertions occurred at Fli1 in both transgenic and nontransgenic tumors. Four insertions were found at a novel locus, termed Fim4, on chromosome 6. This region is syntenic to human 7q32, a region that is commonly deleted in human myelodysplastic syndrome and acute myeloid leukemia. A murine BAC containing Fim4 was sequenced and analyzed, and while there was significant human-mouse homology in the area of the insertions, no candidate gene has been identified. Thus we have established a system to identify genes involved in myelomonocytic tumors, and have used it to identify Fim4, a new common site of proviral insertion. Study of this locus may provide insight into genes involved in AML-associated 7q32 deletions in humans.