Translocation (3;16)(q27;p11) in a Patient with Diffuse Large B-Cell Lymphoma Associated with the BCL-6 Gene Rearrangement

Ichinohasama, Ryo; Miura, Ikuo; Shishido, T.; Matsumoto, Kunihiro; Shimizu, Yoshinaka; Miki, Tohru; DeCoteau, John F.; Kadin, Marshall E.; Ooya, Kiyoshi

doi:10.1016/s0165-4608(97)00390-7

Cited by 5 publications

(4 citation statements)

References 46 publications

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“…4 However, not only point mutations but also somatic hypermutation within germinal centers, leading to structural alterations of the Ig variable genes, may promote translocations as in the case of follicular lymphoma, endemic Burkitt's lymphoma, and certain translocations in diffuse large B-cell lymphomas, eg, t (3;14), involving the bcl-6 gene. 6,14,24,36 In this respect, non-Ig genes linked to transcriptional initiation in mutating normal germinal center B cells may also be permissible in the hypermutation process as recently found for the bcl-6 gene, which is heavily mutated in normal memory B cells but not mutated in naive human B lymphocytes. 52 The necessity of a DNA repair mechanism involved in microdeletion through error-prone repair 13 or by correcting the unmutated complementary to the mutated base 7 and their defects offers another phase of the link between somatic hypermutation of Ig variable genes and lymphoma development.…”

Section: Are Germinal Centers Pathogenic Hot Spots Of Lymphoma Develomentioning

confidence: 80%

Molecular Analysis of Human Immunoglobulin Heavy Chain Variable Genes (IgVH) in Normal and Malignant B Cells

Müller‐Hermelink

Greiner

1998

The American Journal of Pathology

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Antigen binding to the membrane-bound immunoglobulin (Ig) receptor is crucial for clonal survival during B cell development and antigenic stimulation of mature B cells. 41 Together with co-stimulatory signals (eg, CD40 and cytokines) it controls B cell proliferation and differentiation. 37 In the past, molecular analysis of Ig genes has been used mostly to prove clonality of a malignant lymphoproliferation. A detailed analysis, however, reveals that much more can be learned because clonal development, selection processes by antigen, and Ig variable gene (IgV) hypermutation leave a fingerprint of individual clonal development and current activities.The quality of antigen binding is determined primarily by recombination events during ontogeny involving VH, D, and JH genes and, later in the development, VL and JL genes as well as subsequent somatic hypermutation of IgVH and IgVL genes during antigenic responses of mature B cells. 49 Signaling by the Ig receptor eventually rescues pre-B cells and proliferating mature B cells from apoptotic cell death. It thereby forms the basis of a lifelong recurring selection process that is reflected by the Ig receptor repertoire and molecular composition of the Ig receptors in B lymphocyte populations of individuals at different ages. The molecular recombination of VH, D, and JH genes in developing B lymphocytes is probably a random process that would lead to a random use of functional VH genes as determined by their frequency in seven different VH gene families. 9 However, positive or negative selection due to differences in antibody binding efficiency or antigen availability lead to relative over-or underrepresentation of distinctive VH families and VH genes in the receptor repertoire of fetal B lymphocytes. Subsequent antigenic exposure to environmental, infectious, or self antigens on an individual and genetic basis further influences clonal sizes of mature B cell families by usage and selection of distinct VH genes, thereby affecting their frequencies in the adult B cell population. The mechanism of somatic hypermutation of IgV genes is still not completely understood. Functionally, it represents the molecular basis of affinity maturation of naive B cell populations after antigenic exposure and interactions. On a molecular basis it consists of a site-specific hypermutability linked to the transcription of IgV genes acting from the 5Ј of the IgV gene promotor to around 1.5 kb downstream. The constant region exon, which is separated from the variable region by several kilobases of intron, is not affected. Mutations consisting mainly of point mutations accumulate within the antigen-binding complementary determining regions (CDR) in a nonrandom pattern. Rarely, duplications and deletions are also found. 15,57 The somatic hypermutation process is dependent on B cell differentiation and maturation. Pregerminal center B cells usually exhibit unmutated germline receptors. Antigen-activated proliferating germinal center B cells show high mutation rates and evidence of ongoing mutati...

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Section: Are Germinal Centers Pathogenic Hot Spots Of Lymphoma Develomentioning

confidence: 80%

Molecular Analysis of Human Immunoglobulin Heavy Chain Variable Genes (IgVH) in Normal and Malignant B Cells

Müller‐Hermelink

Greiner

1998

The American Journal of Pathology

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“…We previously showed that the majority of lymphoma cells of no. 1012 had t(3;16) as the sole chromosome abnormality, indicating that the translocation was the primary genetic abnormality in this particular case (Ichinohasama et al, 1998). In contrast, YM cells carried a t(2;18)(p11;q21) leading to the fusion between BCL2 and the IG k-light chain gene (Yonetani et al, 1998), raising the possibility that the t(3;16) was a secondary change that developed in a prelymphomatous B-cell with BCL2 translocation and was related to progression to¯orid lymphoma.…”

Section: Of Three Independent Experimentsmentioning

confidence: 83%

“…Cytogenetic and molecular analysis of YM cells revealed that the cells carried t(3;16)(q27;p11) and t(2;18)(p11;q21) involving BCL6 and BCL2, respectively (Yonetani et al, 1998 (Ichinohasama et al, 1998). The cell lines used in the present study were cultured in RPMI 1640 medium supplemented with 10% fetal calf serum (FCS) under the standard culture conditions.…”

Section: Cellsmentioning

confidence: 99%

The gene for interleukin-21 receptor is the partner of BCL6 in t(3;16)(q27;p11), which is recurrently observed in diffuse large B-cell lymphoma

et al. 2002

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BCL6 translocation aecting the chromosomal band 3q27 can involve a number of non-immunoglobulin (non-IG) gene loci as partners. We report here that the gene for interleukin-21 receptor (IL-21R) is the partner of BCL6 in t(3;16)(q27;p11) translocation. The two breakpoints on 16p11 of a lymphoma cell line YM and case no. 1012 with diuse large B-cell lymphoma, both of which carried t(3;16), were localized within the *27-kb intron 1 of IL-21R. As a result of t(3;16), the promoter region of IL-21R was substituted for the regulatory sequences of BCL6 in the same transcriptional orientation. Reverse transcriptase-mediated polymerase chain reaction revealed chimeric mRNA consisting of two noncoding exons 1a/1b of IL-21R and coding exons of BCL6 in both lymphoma cells. Fluorescence in situ chromosomal hybridization of YM metaphase cells revealed fusion signals that contained both the BCL6 and IL-21R sequences on the der(3)t(3;16) chromosome. IL-21R was actively transcribed in YM cells, while BCL6 that was under the control of the IL-21R promoter was only moderately expressed at the mRNA and protein level. We constructed expression plasmid of BCL6 that followed the promoter sequences of IL-21R. COS-7 cells transiently transfected with the plasmid expressed high level Bcl-6 protein and displayed nuclear staining with a characteristic punctate pattern by immuno¯uorescence, indicating that expression of BCL6 can be enhanced by t(3;16). This study added to the list of non-IG partners of BCL6 translocations a new class of gene, i.e. cytokine receptor gene, the expression of which is closely associated with lymphoid cells.

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“…Flow cytometric analysis was carried out according to the method of Ichinohasama et al 19,20 with some modifications using CYTORON ABSOLUTE TM (Ortho Diagnostic Systems, Tokyo, Japan). Antibodies used were specific for CD2 (T11; Beckman Coulter), CD3 (UCHT1; Beckman Coulter), CD4 (T4; Beckman Coulter), CD5 (Lue1; Beckton Dickinson Immunocytometry Systems, San Jose, CA, USA), CD7 (T55; Nichirei, Tokyo, Japan), CD8 (T8; Beckman Coulter), CD10 (J5; Beckman Coulter), CD13 (WM15; Pharmingen, San Diego, CA, USA), CD14 (Mo2; Beckman Coulter), CD16 (3G8; Pharmingen), CD19 (CLB‐CD19; Nichirei), CD20 (NU‐B2; Nichirei), CD33 (WH53; Pharmingen), CD34 (HPCA‐2; Beckton Dickinson), CD56 (B159; Pharmingen), HLA (human leukocyte antigen)‐DR (L243; Beckton Dickinson).…”

Section: Methodsmentioning

confidence: 99%

Blastic natural killer cell lymphoma arising from the mediastinum with terminal deoxynucleotidyl transferase expression

Isobe

Tamaru

Nakamura

et al. 2001

Pathology International

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Blastic natural killer (NK) cell lymphoma/leukemia is a relatively rare NK cell malignancy. We report the second case of blastic NK cell lymphoma arising from the mediastinum with an aggressive clinical course. The patient was a 63-year-old Japanese man with an anterior mediastinum tumor. The biopsy specimen showed diffuse proliferation of tumor cells with frequent mitotic figures and apoptotic bodies. Both angiocentric features and small foci of coagulative necrosis were found in this section. The tumor cells had medium to large nuclei with a fine chromatin pattern, inconspicuous nucleoli and scanty cytoplasm. The nuclear contour was oval to moderately irregular, showing slight pleomorphism as compared with typical lymphoblastic lymphoma. The tumor cells were positive for CD2, CD56 and terminal deoxynucleotidyl transferase, but negative for other T-cell antigens, B-cell antigens and myeloid markers. In situ hybridization for Epstein-Barr virus encoded small ribonucleic acid 1 was negative.

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Translocation (3;16)(q27;p11) in a Patient with Diffuse Large B-Cell Lymphoma Associated with the BCL-6 Gene Rearrangement

Cited by 5 publications

References 46 publications

Molecular Analysis of Human Immunoglobulin Heavy Chain Variable Genes (IgVH) in Normal and Malignant B Cells

Molecular Analysis of Human Immunoglobulin Heavy Chain Variable Genes (IgVH) in Normal and Malignant B Cells

The gene for interleukin-21 receptor is the partner of BCL6 in t(3;16)(q27;p11), which is recurrently observed in diffuse large B-cell lymphoma

Blastic natural killer cell lymphoma arising from the mediastinum with terminal deoxynucleotidyl transferase expression

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