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.
Chromosome 12q24.1 is a recurrent breakpoint in high-grade B-cell 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 12q24.1 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.
Zani
V J
VJ
Academic Department of Haematology and Cytogenetics, Institute of Cancer Research-Royal Marsden Hospital, Sutton, Surrey, UK.
Asou
N
N
Jadayel
D
D
Heward
J M
JM
Shipley
J
J
Nacheva
E
E
Takasuki
K
K
Catovsky
D
D
Dyer
M J
MJ
D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000473:pathology; D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000473:pathology; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics / Q000648:ultrastructure*; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics / Q000648:ultrastructure*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics / Q000648:ultrastructure*; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005796:Genes; D016259:Genes, myc; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics / Q000473:pathology; D008840:Microfilament Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000473:pathology; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
C098982:BCL7A protein, human; D002148:Calmodulin-Binding Proteins; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion