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

Abstract

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.

Comprehensive molecular profiling of 718 Multiple Myelomas reveals significant differences in mutation frequencies between African and European descent cases

“…Three of the genes with significantly higher mutation frequency in AA are involved in other B-cell malignancies. BCL7A has been shown to be directly involved in a three-way gene translocation with Myc and IgH in high-grade B-cell non-Hodgkin lymphoma cell lines [ 30 ]. As a result of the gene translocation, the N-terminal region of the gene product is disrupted, which is thought to be related to the pathogenesis of a subset of high-grade B cell non-Hodgkin lymphoma [ 30 ].…”

“…BCL7A has been shown to be directly involved in a three-way gene translocation with Myc and IgH in high-grade B-cell non-Hodgkin lymphoma cell lines [ 30 ]. As a result of the gene translocation, the N-terminal region of the gene product is disrupted, which is thought to be related to the pathogenesis of a subset of high-grade B cell non-Hodgkin lymphoma [ 30 ]. The protein encoded by BRWD3 is a bromodomain and WD repeat containing protein that is thought to have chromatin-modifying function, and may play a role JAK/STAT pathway activity [ 31 ].…”

An in vivo screen identifies ependymoma oncogenes and tumor-suppressor genes

“…We also identified new ependymoma oncogenes ( BCL7C and ZNF668 ) and TSGs ( TET1 , CDK19, STAG1 and DNA2 ) that regulate chromatin modification and remodeling, or telomere maintenance. These data are particularly interesting since aggressive forms of ependymoma possess aberrant chromatin states 7 and dysfunctional telomeres 36 : BCL7C is a close relative of the lymphoma translocation partner BCL7A 37 and a subunit of the nucleosome remodeling SWI/SNF complex 11 ; ZNF668 links chromatin relaxation state with the DNA damage response 10 ; TET1 is a known TSG that converts 5-methylcytosine into 5-hydroxymethylcytosine 18 ; and CDK19 represses C/EP2β target gene transcription 27 . With regard to telomere function, STAG1 encodes a component of the cohesion complex that is essential for telomere cohesion 26 , while DNA2 recognizes and cleaves telomeric G4, protecting cells from chromosome segregation errors 16 .…”

The Tumor Suppressor BCL7B Functions in the Wnt Signaling Pathway

“…A number of studies have found that BCL7 family members are involved in cancer initiation, progression, and development. For example, decreased expression of BCL7A may be a risk factor for astrocytoma [11] , Burkitt lymphoma [12] , non-Hodgkin's lymphoma [13] , mycosis fungoides [14] , and cutaneous T cell lymphoma [15] . Although the BCL7 gene family is thought to have tumor-associated functions, little is known regarding the specific functional roles of BCL7 genes; this may be attributed to the functional redundancy among BCL7 family members, which makes it difficult to analyze the individual roles of BCL7 genes.…”