Genomic organization of IgH gene compared with the expression of Bcl-2 gene in t(14;18)-positive lymphoma

Amakawa, Ryuichi; Fukuhara, Shirou; Ohno, Hitoshi; F, Matsuyama; Kato, Isoroku; Tanabe, Shoko; Sideras, Pascalis; Mizuta, Tatsunobu-Ryushin; Honjo, Tasuku; Okuma, Minoru

doi:10.1182/blood.v77.9.1970.1970

Cited by 10 publications

(9 citation statements)

References 28 publications

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“…It has been shown that class switching of the translocated IGH allele is relatively common in follicular lymphomas (Cleary and Sklar, 1985;Tsujimoto et al, 1985b;Bakhshi et al, 1987;Amakawa et al, 1991;Kadowaki et al, 1995b), and this observation has been attributed to the fact that follicular lymphomas have many features typical of B cells found in the germinal center, presumably the normal site for class switch events (Cleary and Sklar, 1985;Kadowaki et al, 1995b). We here unambiguously showed by the new LD-PCR approach that 79% (41 of 52) of cases had class switch recombination to C␥ constant genes and 4% (2 of 52) to C␣ genes.…”

Section: Class Switch Recombination On the Der(14) Chromosomementioning

confidence: 99%

“…Furthermore, no follicular lymphoma cells were found to express ␣-heavy chain, implying class switching to a C␣ constant gene on the productive allele. Thus, it is possible that t(14;18) creates an instability within the IGH that is alleviated by deletion of the Cµ gene (Cleary and Sklar, 1985) or, although this is a very speculative alternative, the translocated BCL2 itself functions in promoting the class switch events (Amakawa et al, 1991;Kadowaki et al, 1995a).…”

Section: Class Switch Recombination On the Der(14) Chromosomementioning

confidence: 99%

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Refinement of theBCL2/immunoglobulin heavy chain fusion gene in t(14;18)(q32;q21) by polymerase chain reaction amplification for long targets

Akasaka

Yonetani

Ohno

et al. 1998

Genes Chromosom. Cancer

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The t(14;18)(q32;q21) translocation, involving the BCL2 gene and junctional segments (JH) of the immunoglobulin heavy chain gene (IGH), constitutes the most common chromosomal translocation in non‐Hodgkin's lymphoma of B‐cell type. Although the breakpoints in BCL2 are largely clustered within the major breakpoint region (MBR) and minor cluster region (mcr), it is known that some breakpoints map away from these regions, resulting in negative amplification of the junctional sequence by polymerase chain reaction (PCR) for <1 kb targets. To circumvent this problem, we applied a novel PCR technology for long DNA targets, long‐distance (LD‐) PCR, to the detection of t(14;18) in clinical materials. Oligonucleotide primers were designed to be quite distant from the two known cluster regions in BCL2, and those for the corresponding IGH were complementary to the enhancer and constant regions. In all 52 cases identified as carrying BCL2/JH fusion by conventional Southern blot analysis, LD‐PCR successfully amplified fragments encompassing the junctions, which were readily identifiable on ethidium bromide‐stained gel. The size of the LD‐PCR products ranged from 3.9 kb to 10.7 kb in MBR/IGH fusion and 1.9 kb to 16 kb in mcr/IGH fusion. Furthermore, we established an LD‐PCR protocol for >20 kb targets, which covered the intervening region between the MBR and mcr. Restriction analysis of the LD‐PCR products revealed that breakpoints in 33 cases fell within the 150 bp‐MBR region, and in 3 cases were within the mcr determined previously by others. In contrast, the breakpoints of the remaining 16 cases were distributed over a large region from the MBR through mcr. Nucleotide sequence analysis of a potential cluster region revealed the presence of an Alu repeat sequence. Restriction analysis of LD‐PCR products with BstEII demonstrated a predominant usage of the JH6 segment (71%) at the BCL2/JH junctions. LD‐PCR using primers for the constant region genes showed that class switch recombination occurred in more than 80% of the IGH genes on the der(14) chromosome. Our study showed that LD‐PCR was capable of detecting virtually any t(14;18) that occurred within the approximately 30 kb region downstream of the MBR, and thus is suitable for initial diagnosis of lymphoma tissues. Furthermore, as amplified fragments obtained by the LD‐PCR contained distinctive regions of BCL2 and IGH, restriction analysis and nucleotide sequencing of the products refined the characteristics of t(14;18). Genes Chromosomes Cancer 21:17–29, 1998. © 1998 Wiley‐Liss, Inc.

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Section: Class Switch Recombination On the Der(14) Chromosomementioning

confidence: 99%

Section: Class Switch Recombination On the Der(14) Chromosomementioning

confidence: 99%

Refinement of theBCL2/immunoglobulin heavy chain fusion gene in t(14;18)(q32;q21) by polymerase chain reaction amplification for long targets

Akasaka

Yonetani

Ohno

et al. 1998

Genes Chromosom. Cancer

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“…In our study, for the first time production of the proinflammatory cytokines TNF-a, IL-1b, IL-6 and IL-8 was investigated by comparison of samples of H. pylori-positive and -negative patients which were matched for the histological degree of inflammation. Cytokine production was investigated at the protein level, as the detection of specific mRNA may not always reflect the availability of the corresponding proteins [11].…”

Section: Introductionmentioning

confidence: 99%

Production of IL-12 in gastritis relates to infection withHelicobacter pylori

Bauditz¹,

Ortner²,

Bierbaum³

et al. 1999

Clinical and Experimental Immunology

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Increased production of proinflammatory cytokines, including tumour necrosis factor-alpha (TNF-alpha), IL-1beta, IL-6 and IL-8, has been demonstrated in Helicobacter pylori-associated gastric mucosal inflammation. IL-12, a newly characterized cytokine, is thought to be a key mediator in host responses to bacterial infections. The aim of this study was to investigate differences in cytokine patterns between H. pylori-positive and -negative gastritis and normal mucosa. Secretion of IL-12, TNF-alpha, IL-1beta, IL-6, IL-8 and IL-10 was measured in 176 patients with chronic gastritis in whole biopsy cultures. Gastritis was graded for chronic inflammation or acute inflammatory activity, respectively, according to the Sydney system. Biopsies with similar scores were matched for analysis from H. pylori-infected and non-infected patients. Secretion of IL-12 was significantly increased in H. pylori-associated gastritis in comparison with H. pylori-negative gastritis (P < 0.0001). In contrast, secretion of TNF-alpha, IL-1beta, IL-6, and IL-8 correlated with the degree of inflammation but was not different between H. pylori-positive and -negative patients. Moreover, IL-10 secretion was found to be higher in H. pylori-positive than in H. pylori-negative patients. IL-12 may play a specific role in H. pylori-associated gastric disease, whereas production of the proinflammatory cytokines TNF-alpha, IL-1beta, IL-6 and IL-8 does not seem to be restricted to H. pylori-induced inflammation. The contra-inflammatory cytokine IL-10 may be a contributor to the chronicity of H. pylori-associated gastritis by impairing clearance of the pathogen.

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“…In an examination of B-cell malignancies of all histologies,Borzillo et al (1987) demonstrated that CS deletion of the non-productive allele occurred in 75% of cases where an isotype class switch had occurred on the productively rearranged ZGH allele. In a study of three t( 14; 18) positive lymphoma cell linesAmakawa et al (1991) found C p deletion on the der(l4) in two lines expressing sIGG but no deletion in a sIGM cell line. T h e unexpected result in the current data was the finding of CS deletion of the non-productive ZGH allele in 75% of sIGM positive FL.…”

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confidence: 99%

“…I49cloning from a single cell line the significance of this finding was not appreciated. Recently,Amakawa et al (1991) have also described the CS deletion of the non-productive allele in 213 cell lines both expressing a sIGG. Since all these observations were made in cell lines it is not clear that they reflect what is occurring in clinical samples.…”

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confidence: 99%

A submicroscopic interstitial deletion of chromosome 14 frequently occurs adjacent to the t(14;18) translocation breakpoint in human follicular lymphoma

Zelenetz

Cleary

Levy

1993

Genes Chromosomes & Cancer

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The t(14;18) chromosomal translocation characteristic of follicular lymphoma (FL) juxtaposes the immunoglobulin heavy chain locus (IGH) and the BCL2 proto-oncogene. The translocation can be readily detected as a non-germline Notl fragment resolved by pulsed-field gel electrophoresis. A benefit of this approach is that it enables examination of the structure of a large region (+/- 300 kb) surrounding the chromosomal breakpoint. In 40/46 cases the observed translocated Notl fragment was smaller than the 680-690 kb expected from published restriction maps of the involved loci suggesting a deletion in the region of the breakpoint. Analysis of the der(14) allele by molecular hybridization demonstrated that in 35/46 cases the mu constant region (C mu) was deleted. Further molecular dissection of the IGH locus demonstrated that this resulted from an interstitial deletion of the der(14) chromosome within the region defined by the mu switch region (S mu) on the 5' side and the epsilon constant region (C epsilon) on the 3' end. Thus, the deletion resembled a class switch (CS) recombination event. Surprisingly, the CS deletion was as common in FL which was sIGM positive (24/33, 72.7%) as in cases where the productive allele had already undergone CS deletion (11/13, 84.6%) suggesting that the observed non-physiologic CS deletion resulted from a cis effect of the chromosomal translocation. Similar interstitial deletions of the non-productive IGH allele were not seen in B cell lymphocytic lymphomas which do not have the t(14;18) translocation. Mapping of the 3' extent of the deletion by an isotype PCR assay demonstrated frequent involvement (11/12 cases) of the gamma 1 constant region (C gamma 1). Analysis of cases in which the deletion was not evident by Southern blotting but detectable by PCR suggested that the CS deletion had occurred in a small subpopulation of FL cells subsequent to the t(14;18) translocation. The biological role of frequent interstitial deletions of the der(14) chromosome in t(14;18)-carrying lymphomas remains to be elucidated.

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Genomic organization of IgH gene compared with the expression of Bcl-2 gene in t(14;18)-positive lymphoma

Cited by 10 publications

References 28 publications

Refinement of theBCL2/immunoglobulin heavy chain fusion gene in t(14;18)(q32;q21) by polymerase chain reaction amplification for long targets

Refinement of theBCL2/immunoglobulin heavy chain fusion gene in t(14;18)(q32;q21) by polymerase chain reaction amplification for long targets

Production of IL-12 in gastritis relates to infection withHelicobacter pylori

A submicroscopic interstitial deletion of chromosome 14 frequently occurs adjacent to the t(14;18) translocation breakpoint in human follicular lymphoma

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