A mouse model for chronic lymphocytic leukemia based on expression of the SV40 large T antigen

PJ (Petra) ter Brugge, Van Ta, Marjolein De Jong - de Bruijn, G Keijzers, AIR (Arne) Maas, Dik van Gent, Rudi Hendriks

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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 T-antigen 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 J(H) segments. 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 IgD(low)CD5(+) and manifested nonrandom usage of V, D, and J segments. V-H regions 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. (Blood. 2009; 114:119-127)
Original languageUndefined/Unknown
Pages (from-to)119-127
Number of pages9
Issue number1
Publication statusPublished - 2009

Research programs

  • EMC MGC-01-12-03
  • EMC MM-02-72-03
  • EMC MM-04-42-02

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