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Upregulation of the SOX5 by promoter swapping with the P2RY8 gene in primary splenic follicular lymphoma

Leukemia volume 21, pages 2221–2225 (2007)Cite this article

The vast majority of follicular lymphomas (FL) originate in lymph nodes and are characterized by a specific oncogenic event, the t(14;18)(q32;q21) translocation, juxtaposing the BCL2 gene on chromosome 18 with the immunoglobulin heavy chain locus on chromosome 14, leading to the overexpression of the antiapoptotic molecule BCL2.1 On the other hand, there is a group of t(14;18)(q32;q21)-negative FLs, mostly found in skin or in other extranodal sites as well as in lymph nodes.2 Follicular center cell lymphomas of the spleen rarely arise as primary splenic follicular lymphoma (PSFL), but involvement of the spleen is common in the context of a generalized lymphoma. To date, there are no data about the biological features of PSFL, due to the sporadic frequency of this pathologic entity. We report a PSFL case showing a novel fusion gene involving P2RY8 (G-protein coupled purinergic receptor P2Y8), and SOX5, one of the Sry (sex-determining region Y)-box (SOX) genes. The fusion was detected by fluorescence in situ hybridization (FISH) and reverse transcription (RT)-PCR. The P2RY8/SOX5 chimera resulted in the overexpression of SOX5 and the encoded protein, evaluated by real-time quantitative PCR (RQ-PCR) and immunohistochemistry, respectively.

None of the three amplified transcripts resulted in a chimeric in-frame P2RY8/SOX5. The fusion breakpoint, in all the three fusion transcripts, mapped before the start of the P2RY8 coding sequence (P2RY8 exon 2) and preserved the SOX5 ATG initiation codon, which begins at the second nucleotide of SOX5 exon 6 (BC060773) (Figure 2e). RT-PCR for the reciprocal SOX5/P2RY8 fusion product, using SOX5 exon 1 forward and P2RY8 exon 2 reverse primers, yielded negative results (data not shown). The expression level of SOX5 was determined by RQ-PCR using 1X PlatinumSYBR Green qPCR SuperMix-UDG (Invitrogen, Carlsbad, CA, USA). Proper primer combinations were used to discriminate among splicing variants. In detail, the SOX5ex6-162F/SOX5ex7-42R allowed the amplification of transcript variant type I only. The other two variants (types 2 and 3) were obtained using SOX5ex6-119F/SOX5ex7-42R (Figures 2d–f). 28S rRNA was used as reference gene and one (no. 3, Figure 2f) of the three normal spleen samples was utilized as calibrator. The gene expression level variation was estimated by comparing the values of □ 2 - ΔΔ C t (relative amount of cDNA) for the SOX5 Ct values in the patient with t(X;12), three cases of nodal FL, and three normal spleen samples, with the relative value of the calibrator. Moreover, the Ct mean values of the three normal spleen samples and the three FL patients were also considered during the analysis. The significance was estimated by comparing the respective ranges ( □ 2 - ΔΔ C t ± s.d. ) of these values (Figure 2f). This analysis revealed a clear upregulation of all the SOX5 splicing variants in the case with the t(X;12) rearrangement (Figure 2f). Immunohistochemical analysis using two different SOX5 antibodies, based on a guinea pig antibody4 and a rabbit anti-SOX5 antibody (Abcam ab26041), showed nuclear overexpression of the SOX5 protein in most of the neoplastic follicular cells (Figure 1e). SOX5 immunoreactivity was absent in five cases of t(14;18) positive FL (data not shown).

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Acknowledgements

This work has been supported by AIRC (Associazione Italiana per la Ricerca sul Cancro), and MIUR (Ministero dell'Istruzione, dell'Università e della Ricerca). We thank Professor M Wegner and Dr L Cimarosto for their contribution to the study, and Ms MVC Pragnell, BA for language revision of this article.

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Authors and Affiliations

  1. Department of Genetics and Microbiology, University of Bari, Bari, Italy

    C T Storlazzi, M C Guastadisegni, L Impera, A Lonoce & M Rocchi

  2. Department of Hematology, University of Bari, Bari, Italy

    F Albano & G Specchia

  3. Servizio di Anatomia Patologica, Ospedale S Martino, Belluno, Italy

    C Lo Cunsolo, S Funes, E Macrì & P Iuzzolino

  4. UO Anatomia Patologica, Istituto Scientifico San Raffaele, Milano, Italy

    C Doglioni

  5. Department of Clinical Genetics, University Hospital, Lund, Sweden

    I Panagopoulos

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  1. C T Storlazzi
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Correspondence to C T Storlazzi.

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Storlazzi, C., Albano, F., Lo Cunsolo, C. et al. Upregulation of the SOX5 by promoter swapping with the P2RY8 gene in primary splenic follicular lymphoma. Leukemia 21, 2221–2225 (2007). https://doi.org/10.1038/sj.leu.2404784

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