Overexpression of SOX5 by a Novel Chromosome Translocation Involving the IGH Locus In a Follicular Lymphoma without BCL2 Expression

Abstract 4453

The majority of follicular lymphoma (FL) cases are characterized by upregulation of BCL2 expression in tumor cells as results of a specific oncogenic event, t(14;18)(q32;q21), or other molecular mechanisms including amplification of the BCL2 gene. Approximately 10% of FL cases are lack of t(14;18)(q32;q21) and BCL2 expression. Molecular pathogenesis of BCL2 negative-FL has not been clarified.

We found a case of BCL2-negative FL with a chromosome abnormalities including t(12;14)(p12;q32). Translocations involving 14q32 are frequently seen in B-lymphoid neoplasms, and breakpoints are often clustered within the IGH gene locus. Chromosome translocations involving the IGH locus represent the molecular mechanism of activation of a number of proto-oncogenes in B-cell neoplasms. In the present case, we hypothesized that as a result of the translocation a target gene on 12p12 is upregulated by juxtaposition to an enhancer region within the IGH gene and may play an important role in lymphoma development. Therefore, we attempted to determine a breakpoint of t(12;14)(p12;q32) by using a long-distance inverse PCR (LDI-PCR). Genomic DNA isolated from a lymph node sample was digested with restriction enzymes. Fragmented DNA was ligated to form circular DNA, and subjected to LDI-PCR. LDI-PCR was carried out using primer sets complementary to regions within the IGH locus. PCR products were subcloned into pGEM-T vector, and sequenced. The sequences were analyzed by a BLAST computational search. We determined the sequence around a breakpoint, in which we found the IGH gene J region on 14q32, as expected, and intron 1 of the SRY-related high-morbidity-group (HMG) box 5 (SOX5) gene on 12p12. In the rearranged chromosome region, an enhancer region within the IGH gene is located to up-stream of the exon 2 of the SOX5 gene. Coding region of the SOX5 genes spans from exons 5 to 20 so that all of coding exons of the SOX5 gene are retained on the rearranged chromosome. We examined SOX5 expression by immunohistochemistry using anti-SOX5 rabbit polyclonal antibody. SOX5 is overexpressed in nuclei of tumor cells in neoplastic follicle.

SOX5 is a member of SOX family transcriptional factors which are characterized by the HMG box DNA binding domain. SOX5 is involved in the regulation of embryonic development and in the determination of the cell fate. In addition, SOX5 may play roles in the pathogenesis of some types of human cancers. In invasive testicular germ cell tumors, in which gain of short arm of chromosome 12 is frequently found, the SOX5 gene amplification is observed. In nasopharyngeal carcinoma, SOX5 overexpression is associated with poor clinical outcome, and SOX5 works as a transcriptional repressor for SPARC which is a putative tumor suppressor gene. These findings suggest that the SOX5 gene is a kind of proto-oncogene. Currently, Storlazzi et al. reported that SOX5 expression is upregulated by promoter swapping with the P2RY8 gene, as a result of t(X;12)(p22;p12) in primary splenic FL without BCL2 expression. Their report and our present result suggest that SOX5 overexpression play a role in BCL2-negative FL development. Further studies are necessary to clarify a molecular biological role of SOX5 overexpression in the pathogenesis of BCL2-negative FL.