A mouse model for chronic lymphocytic leukemia based on expression of the SV40 large T antigen
The simian virus 40 (SV40) T antigen is a potent oncogene able to transform many cell types and has been implicated in leukemia and lymphoma. In this report, we have achieved sporadic SV40 Tantigen expression in mature B cells in mice, by insertion of a SV40 T antigen gene in opposite transcriptional orientation in the immunoglobulin (Ig) heavy (H) chain locus between the D and JHsegments. SV40 T-antigen expression appeared to result from retention of the targeted germline allele and concomitant antisense transcription of SV40 large T in mature B cells, leading to chronic lymphocytic leukemia (CLL). Although B-cell development was unperturbed in young mice, aging mice showed accumulation of a monoclonal B-cell population in which the targeted IgH allele was in germline configuration and the wild-type IgH allele had a productive V(D)J recombination. These leukemic B cells were IgDlowCD5and manifested nonrandom usage of V, D, and J segments. VHregions were either unmutated, with preferential usage of the VH11 family, or manifested extensive somatic hypermutation. Our findings provide an animal model for B-CLL and show that pathways activated by SV40 T antigen play important roles in the pathogenesis of B-CLL.
|Persistent URL||dx.doi.org/10.1182/blood-2009-01-198937, hdl.handle.net/1765/25324|
ter Brugge, P.J., Ta, T.B.V., de Bruijn, M.J.W., Keijzers, G., Maas, A., van Gent, D.C., & Hendriks, R.W.. (2009). A mouse model for chronic lymphocytic leukemia based on expression of the SV40 large T antigen. Blood, 114(1), 119–127. doi:10.1182/blood-2009-01-198937