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

TY - JOUR

T1 - A mouse model for chronic lymphocytic leukemia based on expression of the SV40 large T antigen

AU - ter Brugge, Petra J

AU - Ta, Van B T

AU - de Bruijn, Marjolein J W

AU - Keijzers, Guido

AU - Maas, Alex

AU - van Gent, Dik C

AU - Hendriks, Rudi W

N1 - Keywords: Alleles; Animals; Antigens, Polyomavirus Transforming; B-Lymphocytes; Disease Models, Animal; Gene Expression; Heterozygote; Humans; Immunoglobulin Heavy Chains; Leukemia, Experimental; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Simian virus 40; Somatic Hypermutation, Immunoglobulin; Tumor Suppressor Protein p53

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1182/blood-2009-01-198937

DO - 10.1182/blood-2009-01-198937

M3 - Journal article

C2 - 19332766

SN - 0006-4971

VL - 114

SP - 119

EP - 127

JO - Blood

JF - Blood

IS - 1

ER -