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

Abstract

IntroductionB-cell chronic lymphocytic leukemia (B-CLL), 1,2 the most common leukemia in the Western world, is characterized by the accumulation of a monoclonal population of mature B cells that aberrantly express CD5. 3,4 The clinical course of CLL is extremely heterogeneous: whereas some patients survive more than a decade with stable disease, others die of the disease within months despite aggressive treatment. This heterogeneity is associated with variability in the expression pattern of a number of different proteins, and also with the presence of different chromosomal aberrations. 5 Approximately half of the CLL cases have 13q14deletions, apparently involving the linked microRNA molecules miR15 and miR16, which are thought to be negative regulators of the antiapoptotic gene Bcl2. 2 Deletions on chromosome 17p, affecting the p53 protein, are less frequent and are associated with poor prognosis. 6,7 CLLs manifest a unique gene-expression signature that differs from other lymphoid cancers, suggesting a common mechanism of transformation or a homogeneous cell population of origin. 2 CLL has been subdivided into 2 prognostic subsets, based on the presence of somatic mutations of the immunoglobulin (Ig) heavy (H) chain variable (V H ) genes. A total of 50% to 70% of CLL patients have mutated V H genes, probably reflecting antigen-driven postgerminal center (GC) selection, and have a more favorable prognosis than those with unmutated B-cell receptors. CLL Ig V H regions also exhibit unique complementarity determining region 3 (CDR3) features that characterize and differentiate aggressive unmutated from more indolent mutated CLLs. In particular, unmutated poor outcome cases frequently contain long CDR3s with amino acid residues that favor polyreactivity. Interestingly, both unmutated and mutated CLLs are thought to derive from self-reactive B-cell precursors. 8 In this context, it has been found that approximately 3% to 4% of healthy persons older than 40 years of age have a population of monoclonal lymphocytes in their blood with immunophenotypic characteristics of CLL cells. 2 The simian virus 40 (SV40) T antigen is a potent oncogene able to transform many cell types 9,10 and has been implicated in the etiology of various cancers. 11,12 The SV40 T antigen has transforming activity by inactivating p53 and Rb proteins and inducing genomic instability. 13 Several studies point to a causative role of SV40 in the formation of human B-cell malignancies, including non-Hodgkin lymphoma. [14][15][16] Transgenic expression of the SV40 T gene under the control of the IgH enhancer induced hyperproliferation of multilineage hematopoiesis, reminiscent of myelodysplastic syndromes in humans. 17 In this report, we aimed to accomplish sporadic SV40 T gene expression in the B-cell lineage in mice. We introduced the SV40 T gene, without its promoter and in opposite transcriptional orientation between the IgH chain D and J H segments. As antisense transcription takes place across the D-J H region in pro-B cells, 18 it is possible t...

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Detection of a novel truncating Merkel cell polyomavirus large T antigen deletion in chronic lymphocytic leukemia cells

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