Cyclin D3 is a target gene of t(6;14)(p21.1;q32.3) of mature B-cell malignancies

• Published in: Blood 2001-11, Vol.98 (9), p.2837-2844
• Main Authors: Sonoki, Takashi, Harder, Lana, Horsman, Doug E., Karran, Loraine, Taniguchi, Izumi, Willis, Tony G., Gesk, Stefan, Steinemann, Doris, Zucca, Emanuele, Schlegelberger, Brigitte, Solé, Francesc, Mungall, Andrew J., Gascoyne, Randy D., Siebert, Reiner, Dyer, Martin J.S.
• Format: Article
• Language: English
• Subjects: Adult; Aged; B-Lymphocytes - chemistry; B-Lymphocytes - pathology; B-Lymphocytes - ultrastructure; Base Sequence; Biological and medical sciences; Chromosome Breakage - genetics; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 6; Cloning, Molecular; Cyclin D3; Cyclins - genetics; Female; Hematologic and hematopoietic diseases; Humans; Immunoglobulin Heavy Chains - genetics; Immunohistochemistry; In Situ Hybridization, Fluorescence; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, B-Cell - chemistry; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - pathology; Lymphoproliferative Disorders - genetics; Lymphoproliferative Disorders - pathology; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Translocation, Genetic - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V98.9.2837

Chromosomal translocation t(6;14)(p21.1;q32.3) has been reported as a rare but recurrent event not only in myeloma and plasma cell leukemia but also in diffuse large B-cell non-Hodgkin lymphoma (B-NHL) (diffuse large B-cell lymphoma [DLBCL]) and splenic lymphoma with villous lymphocytes (SLVL); however, the nature of the target gene(s) has not been determined. This study identified t(6;14)(p21.1;q32.3) in 3 cases of transformed extranodal marginal zone B-NHL, in 1 case of SLVL, and in 1 case of a low-grade B-cell lymphoproliferative disorder. In a sixth case, a CD5+ DLBCL, the translocation was identified by molecular cloning in the absence of cytogenetically detectable change. Two chromosomal translocation breakpoints were cloned by using long-distance inverse polymerase chain reaction methods. Comparison with the genomic sequence for chromosome 6p21.1 showed breakpoints approximately 59 and 73.5 kilobases 5′ of the cyclin D3 (CCND3) gene with no other identifiable transcribed sequences in the intervening region. Although Southern blotting with derived genomic 6p21.1 probes failed to detect other rearrangements, fluorescent in situ hybridization assays, using BAC (bacterial artificial chromosome) clones spanning and flanking theCCND3 locus, along with probes for IGHconfirmed localization of 6p21.1 breakpoints within the same region, as well as fusion of the CCND3 and IGH loci. Furthermore, in all cases, high-level expression of CCND3was demonstrated at RNA and/or protein levels by Northern and Western blotting and by immunohistochemistry. These data implicateCCND3 as a dominant oncogene in the pathogenesis and transformation in several histologic subtypes of mature B-cell malignancies with t(6;14)(p21.1;q32.3) and suggest thatCCND3 overexpression seen in about 10% of DLBCL cases may have a genetic basis.