Molecular Cloning of Complex Chromosomal Translocation t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt Lymphoma Cell Line Defines a New Gene (BCL7A) With Homology to Caldesmon

• Published in: Blood Vol. 87; no. 8; pp. 3124 - 3134
• Main Authors: Zani, V.J., Asou, N., Jadayel, D., Heward, J.M., Shipley, J., Nacheva, E., Takasuki, K., Catovsky, D., Dyer, M.J.S.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-04-1996; The Americain Society of Hematology
• Subjects: Amino Acid Sequence; B-Lymphocytes - pathology; Base Sequence; Biological and medical sciences; Burkitt Lymphoma - genetics; Burkitt Lymphoma - pathology; Calmodulin-Binding Proteins - genetics; Chromosomes, Human, Pair 12 - genetics; Chromosomes, Human, Pair 12 - ultrastructure; Chromosomes, Human, Pair 14 - genetics; Chromosomes, Human, Pair 14 - ultrastructure; Chromosomes, Human, Pair 8 - genetics; Chromosomes, Human, Pair 8 - ultrastructure; Cloning, Molecular; DNA, Complementary - genetics; DNA, Neoplasm - genetics; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Genes; Genes, myc; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Non-Hodgkin - genetics; Lymphoma, Non-Hodgkin - pathology; Medical sciences; Microfilament Proteins - genetics; Molecular Sequence Data; Neoplasm Proteins - genetics; Neoplastic Stem Cells - pathology; Oncogene Proteins; Oncogene Proteins, Fusion - genetics; Sequence Alignment; Sequence Homology, Amino Acid; Tumor Cells, Cultured; Chromosomal aberration; Pathogenesis; Homology; Abnormal chromosome C8; Gene; Lymphoproliferative syndrome; Established cell line; Genetics; Molecular cloning; Chromosome translocation; Human; Enzyme; Transferases; Burkitt lymphoma; Exploration; Malignant hemopathy; B-Lymphocyte; Non Hodgkin lymphoma; Infection; Caldesmon kinase; Viral disease; Gene rearrangement; Abnormal chromosome; Abnormal chromosome C12; Molecular biology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V87.8.3124.bloodjournal8783124

Chromosome 12q24.1 is a recurrent breakpoint in high-grade B-cetl non-Hodgkin lymphoma (B-NHL). To identify the genes involved at 12q24.1, molecular cloning of a three-way translocation t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt lymphoma cell line (Wien 133) was performed; all four translocation breakpoints were cloned and sequenced. Analysis of clones encompassing the der(12)(12;14)(q24.1;q32.3) breakpoint showed a CpG island from chromosome 12q24.l juxtaposed in a tail-to-tail configuration with a productively rearranged Ig VH4-DH-JH5 gene. A total of 4.5 kb of genomic DNA including the CpG island was sequenced and analyzed using gene-identification programs; all three programs identified a potential 92-bp exon within the centromeric boundary of the CpG island. Using this as a probe, an RNA transcript of 3.8 kb, expressed at low levels in a wide variety of normal tissues, was detected. Overlapping cDNA clones were isolated and sequenced. The longest open-reading frame predicted a serine-rich protein of 231 amino acids. This protein, termed BCL7A, exhibited no recognizable protein motifs but showed homology with the actin-binding protein, caldesmon. In Wien 133, the BCL7A breakpoint occurred within the first intron and resulted in a MYC-BCL7A fusion transcript, with exon I of BCL7A being replaced by MYC exon I. The normal, untranslocated allele of BCL7A was also expressed without mutation. One of the 11 other B-NHL cell lines examined with 12q24.1 cytogenetic abnormalities, a mediastinal B-NHL cell line (Karpas 1106), showed biallelic rearrangement within the first intron of BCL7A, which was adjacent to the breakpoint observed in Wien 133. Disruption of the amino-terminus of BCL7A defines a new mechanism in the pathogenesis of a subset of high-grade B-NHL.