Activation of Stat5a by retrovirus integration induces early B-cell lymphomas in SL/Kh mice.

H Hiai, MD,PhD, T.Tsuruyama, MD, T. Nakamura, MD, PhD

Kyoto University Graduate School of Medicine, Kyoto, Kyoto Japan

[AIM] We aims at elucidation of virus-host interaction in development of early B-cell lymphomas in SL/Kh strain mice. In SL/Kh BM, transient polyclonal expansion of pre-B cells was seen at 4-6 weeks of age, and subsequent monoclonal growth, after 12 weeks of age. The transient pre-B-cell expansion is directed by a QTL Bomb1 on chromosome 3 and the monoclonal growth, by re-integration of endogenous MuLV genomes. [METHODS] To elucidate the molecular mechanism of lymphoma-genesis, virus-host junction fragments were isolated from lymphoma DNAs by inverse PCR, sequenced and analyzed by BLAST. Expression of genes were examined by either RT-PCR, Western or Northern blot. [RESULTS] We found that the second intron of Stat5a was one of the common integration sites of the endogenous ecotropic murine leukemia virus (MuLV), i.e., Svi1 (SL/Kh virus integration-1) in 3 out of 60 early B-cell lymphomas of SL/Kh mice. The lymphomas with Svi1 integration had more immature phenotype than the majority of SL/Kh lymphomas. High expression of STAT5A was induced by Svi1 integration to accelerate the transcription of its target genes such as Pim-1, Bcl-xL, and c-Myc. Transfection of the constitutively activated Stat5a mutant cDNA, but not willd type cDNA, to the BM cells induced colony formation of pro-B cells in a methylcellulose medium and their immortalization. Such immortalization was dependent on SL/Kh genetic background. [CONCLUSION] Provirus integration to Svi1 thus induced pro-B lymphomagenesis by activation of the Stat5a in collaboration with an unknown host factor.

KEY WORDS: Retrovirus, Integration, Hot spot, Stat5a, Pro-B lymphoma.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Viral Oncogenesis.