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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

Leukemia volume 16, pages 1827–1834 (2002)Cite this article

Abstract

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.

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Acknowledgements

This work was performed with a grant from the American Cancer Society to ASP (No. DB93–074). We thank David Skalnik for providing the gp91phox–SV40 early region transgene construct, Daniel Gien, Valerie Green, William Chen, Linda Cleveland, Janet Grubber, and Bryn Eagleson for technical assistance, and Robert M Kovatch for pathologic diagnosis. We also thank Sandra Ruscetti for supplying the F-MuLV env probe, Sandy Morse for providing the IgH probe, and Eric Rassart for providing the Fli1 probe. We also thank JoAnn Falato for secretarial support.

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Authors and Affiliations

  1. Department of Pathology, Yale University, New Haven, CT, USA

    J Kone, J Arroyo, T Savinelli, S Lin, K Boyd & AS Perkins

  2. Department of Genetics, Yale University, New Haven, CT, USA

    M Nimmakayalu & M Qumsiyeh

  3. Department of Laboratory Medicine, Yale University, New Haven, CT, USA

    Y Wu

  4. Laboratory of Mammalian Genetics, NCI, Frederick, MD, USA

    NG Copeland & NA Jenkins

  5. Department of Chemistry and Biochemistry, Oklahoma University, Norman, OK, USA

    P Hu, A Prescott, H Wu, L Yang & B Roe

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Kone, J., Arroyo, J., Savinelli, T. et al. 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. Leukemia 16, 1827–1834 (2002). https://doi.org/10.1038/sj.leu.2402598

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