Identification of Potential Human Oncogenes by Mapping the Common Viral Integration Sites in Avian Nephroblastoma

Abstract

Gene deregulation is a frequent cause of malignant transformation. Alteration of the gene structure and/or expression leading to cellular transformation and tumor growth can be experimentally achieved by insertion of the retroviral genome into the host DNA. Retrovirus-containing host loci found repeatedly in clonal tumors are called common viral integration sites (cVIS). cVIS are located in genes or chromosomal regions whose alterations participate in cellular transformation. Here, we present the chicken model for the identification of oncogenes and tumor suppressor genes in solid tumors by mapping the cVIS. Using the combination of inverse PCR and long terminal repeat-rapid amplification of cDNA ends technique, we have analyzed 93 myeloblastosisassociated virus type 2-induced clonal nephroblastoma tumors in detail, and mapped >500 independent retroviral integration sites. Eighteen genomic loci were hit repeatedly and thus classified as cVIS, five of these genomic loci have previously been shown to be involved in malignant transformation of different human cell types. The expression levels of selected genes and their human orthologues have been assayed in chicken and selected human renal tumor samples, and their possible correlation with tumor development, has been suggested. We have found that genes associated with cVIS are frequently, but not in all cases, deregulated at the mRNA level as a result of proviral integration. Furthermore, the deregulation of their human orthologues has been observed in the samples of human pediatric renal tumors. Thus, the avian nephroblastoma is a valid source of cancerassociated genes. Moreover, the results bring deeper insight into the molecular background of tumorigenesis in distant species. (Cancer Res 2006; 66(1): 78-86)

Potentially oncogenic B-cell activation–induced smaller isoforms of FOXP1 are highly expressed in the activated B cell–like subtype of DLBCL

“…In this model system, foxP1 was the second most frequent target of retroviral insertion, occurring in 5% of the tumor clones. 28 Within the context of the current study, of particular interest were the observations that these insertions did not affect foxP1 mRNA levels and that they all clustered within the second coding exon, causing a putative NH 2 -terminal deletion. This led Pajer et al to propose that, "the virally altered foxP1 might interfere (in a dominant-negative fashion) with a normal function of the gene and support malignant transformation."…”

FOXP1 abnormalities in lymphoma: translocation breakpoint mapping reveals insights into deregulated transcriptional control

“…In one study FOXP1 was one of the most frequent targets of retroviral integration in myeloblastosisassociated virus type-2-induced chicken nephroblastoma. 18 Significantly, all the integration events were clustered around the second coding exon (corresponding to human FOXP1 exon 7). 18 Typically, the retrovirus exerts its oncogenic potential by deregulating cellular gene expression or causing alterations in the cellular gene product, consequently changing its function.…”

N-terminally truncated FOXP1 protein expression and alternate internal FOXP1 promoter usage in normal and malignant B cells

“…25 Also, we have described abundant expression of short 65kDa activation-induced FOXP1 proteins (FOXP1 S ) in ABC-DLBCL. 26 Oncogenic activity of N-terminally truncated FOXP1 has been proposed following its truncation by an oncogenic virus 27 and non-IGH translocations targeting the FOXP1 coding region in lymphoma. 24,28,29 Studies manipulating Foxp1 expression have established biological roles in early B-cell development 30,31 and in mature B cells.…”