title: A mouse model for chronic lymphocytic leukemia based on expression of the SV40 large T antigen.
abstract: 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.
authors.affiliation: Departments of Immunology, Erasmus MC Rotterdam, Rotterdam, The Netherlands.
authors.forename: Petra J
authors.initials: PJ
authors.lastname: ter Brugge
authors.forename: Van B T
authors.initials: VB
authors.lastname: Ta
authors.forename: Marjolein J W
authors.initials: MJ
authors.lastname: de Bruijn
authors.forename: Guido
authors.initials: G
authors.lastname: Keijzers
authors.forename: Alex
authors.initials: A
authors.lastname: Maas
authors.forename: Dik C
authors.initials: DC
authors.lastname: van Gent
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks