High-Throughput Retroviral Tagging for Identification of Genes Involved in Initiation and Progression of Mouse Splenic Marginal Zone Lymphomas

Abstract

Human B-cell lymphomas are frequently associated with specific genetic changes caused by chromosomal translocations that activate protooncogenes. For lymphomas of mice expressing murine leukemia virus, mutagenic proviral insertions are thought to play a similar role. Here we report studies designed to determine whether specific retroviral integration sites might be associated with a specific subset of mouse B-cell lymphomas and if the genes associated with these sites are regularly altered in expression. We studied splenic marginal zone lymphomas (MZL) of NFS.V ؉ mice that are unusual in exhibiting frequent progression from low to high grade, potentially allowing assignment of cancer genes to processes of initiation and progression. We used inverse PCR to clone and analyze 212 retroviral integration sites from 43 MZL at different stages of progression. Sixty-two marked common integration sites and included 31 that had been marked previously. Among the new common integration sites, seven were unique to MZL. Using microarrays and real-time quantitative PCR analysis, we defined differential patterns of gene expression in association with disease progression for Gfi1, Sox4, Brca2, Snf1lk, Nfkb1, Pou2af1, Prdm1, Stat6, and Blnk. Heightened expression of Gfi1 distinguishes MZL from other lymphoma types. The combined use of proviral tagging and analyses of gene expression thus provides a powerful approach to understanding of genes that collaborate in tumorigenesis.

Nuclear expression of sox11 is highly associated with mantle cell lymphoma but is independent of t(11;14)(q13;q32) in non-mantle cell B-cell neoplasms

“…20,21 High-throughput retroviral tagging identified that SOX4 expression was elevated in Sox11 in B-cell neoplasms mouse splenic marginal zone lymphoma and associated with tumor progression. 22 In this study, we showed that the nuclear expression of sox11 is highly associated with mantle cell lymphoma among B-cell lymphomas. Homogeneous nuclear staining of sox11 was observed in 54 of 57 (95%) mantle cell lymphomas, including 52 of 53 (98%) classical and 2 of 4 variant mantle cell lymphomas.…”

Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-transgenic mice

“…In contrast to other studies using the MMLV or in the AKXD or BXH2 inbred mouse lines to accelerate pre-T and pre-B lymphomas or myeloid leukemias (Li et al, 1999;Hwang et al, 2002;Kim et al, 2003;Erkeland et al, 2004;Iwasaki et al, 2004;Shin et al, 2004), this approach exploited the preferential tropism of the mAIDS virus for mature B lymphocytes and successfully accelerated cancer progression in IgHm-HOX11 Tg mice. The relatively low number of integrations observed (B1.9 per tumor) is consistent with reports that the Du5H mAIDS virus yields fewer (between 2 and 4) integration events when compared to MMLV (between 6 and 10) or with other models of recombinant inbred mouse strains characterized by laterally transmitted retroviruses (Huang et al, 1995).…”

“…Retroviral-derived DNA sequences that integrate adjacent to cellular oncogenes or within coding regions of tumor suppressors, can result in altered host gene expression contributing, ultimately, to clonal expansion of the infected cell. While the proviral tagging approach has resulted in the discovery of many genes involved in lymphoid and myeloid leukemias (Li et al, 1999;Hwang et al, 2002;Kim et al, 2003;Erkeland et al, 2004;Iwasaki et al, 2004;Shin et al, 2004), less work has been conducted on mature B-cell lymphomas.…”

Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output

“…In addition, Sox4 appears to have a dominant role in conferring oncogenic and metastatic transformation (Rhodes et al, 2004). High levels of Sox4 mRNA expression have been observed in a large number of human tumors including breast, lung, brain, prostate and ovarian cancer, and the Sox4 gene locus has been repeatedly found to be targeted by tumor-promoting retroviral integration in mice (Lund et al, 2002;Suzuki et al, 2002;Shin et al, 2004). Together, these studies support the inclusion of Sox4 as one of the 64 genes that constitute a general cancer signature (Rhodes et al, 2004).…”