Aberrant Somatic Hypermutation in Extranodal Marginal Zone B-Cell Lymphoma of MALT Type.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 417-417 ◽  
Author(s):  
Alexander Deutsch ◽  
Ariane Aigelsreiter ◽  
Christine Beham-Schmid ◽  
Alfred Beham ◽  
Werner Linkesch ◽  
...  
Keyword(s):  
B Cell ◽  
Malt Lymphoma ◽  
Marginal Zone ◽  
De Novo ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Chromosomal Translocations ◽  
Genome Wide ◽  
Balanced Translocations

Abstract Extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma) accounts for approximately 7% to 8% of all non-Hodgkin lymphomas (NHLs) being the third most frequent histological subtype. The gastrointestinal tract - particularly the stomach - is the most common site of MALT lymphoma comprising 50% of all cases, but virtually every organ may be affected by this type of lymphoma. Transformation (or de novo emergence at extranodal sites) in diffuse large B-cell lymphoma (DLBCL) occurs but - according to the WHO criteria - is considered as separate entity. The understanding of the molecular biology of MALT lymphoma has significantly improved following the recent cloning of recurrent balanced translocations such as t(11;18) or t(14;18), but a mechanism for genome-wide instability during MALT lymphomagenesis has not been described. We have reported that the somatic hypermutation process (SHM) physiologically aimed at mutating the immunoglobulin variable gene (IgV) aberrantly targets multiple proto-oncogenes in >50% of DLCBL (Pasqualucci et al., Nature412:341, 2001). Consequently, multiple mutations are introduced in the 5′ region of genes including known proto-oncogenes such as PIM-1, PAX-5, Rho/TTF and c-MYC. To further investigate whether aberrant somatic hypermutation (ASHM) also occurs in MALT lymphoma, we studied the mutation profile of these genes in 17 MALT lymphomas (6 of gastric- and 11 of nongastric origin) and 18 extranodal DLBCL (10 gastric, 8 nongastric). Mutations in one or more genes were detected in 15 of 17 (88.2%) cases of MALT lymphoma and in all of 18 (100%) cases of extranodal DLBCL. 7 of 17 (41.2%) and 15 of 18 (83.3%) carried mutations in two or more genes in the MALT- and DLBC-lymphoma group, respectively. Overall, mutations in PIM-1 occurred in 5 of 17 (29.4%) cases with MALT lymphoma and in 10 of 18 (55.5%) in extranodal DLBCL cases. For PAX-5, the distribution of mutated cases between MALT- and DLBC-lymphoma was 6 of 17 (35.3%) and 10 of 18 (55.5%), for Rho/TTF 3 of 17 (17.6%) and 8 of 18 (44.4%) and for c-MYC 9 of 17 (52.9%) and 12 of 18 (66.6%), respectively. A total of 99 sequence variants were found in 35 cases, 29 in the MALT lymphomas and 70 in extranodal DLBCL. Although the mutations were almost exclusively single base pair substitutions (n=98 ), an insertion was also present (n=1). Mutations were of somatic origins, occur independent of chromosomal translocations to the Ig loci and share features of the IgV SHM process including bias for transition over transversion, preferential hotspot (RGYW/WRCY) targeting and restriction to the first 1–2Kb from the promoter. The mean mutation frequency in mutated MALT lymphomas was with 0.045 x10−2/bp 1.7 fold lower compared to 0.08 x10−2/bp in mutated extranodal DLBCL. Further in PIM-1, PAX-5 and c-MYC some of the mutations were found to affect coding exons, leading to amino acid exchanges, thus potentially altering gene function. These data indicate that aberrant SHM is associated with extranodal DLBCL and MALT lymphoma, likewise. By mutating regulatory and coding sequences of the targeted genes and by possibly favouring chromosomal translocations ASHM may represent a major contributor to their pathogenesis. ASHM may further support a model of MALT lymphomagenesis leading from an antigen driven lesion to transformed MALT lymphoma finally evolving to overt DLBCL.

scholarly journals A phase II study of lenalidomide in patients with extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT lymphoma)

Haematologica ◽  
2012 ◽  
Vol 98 (3) ◽  
pp. 353-356 ◽  
Author(s):  
B. Kiesewetter ◽  
M. Troch ◽  
W. Dolak ◽  
L. Mullauer ◽  
J. Lukas ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Malt Lymphoma ◽  
Lymphoid Tissue ◽  
Marginal Zone ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma

Aberrant Somatic Hypermutation Targets an Extensive Set of Genes in Diffuse Large B-Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1528-1528 ◽  
Author(s):  
Laura Pasqualucci ◽  
Roberta Guglielmino ◽  
Sami N. Malek ◽  
Urban Novak ◽  
Mara Compagno ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Chromosomal Translocations ◽  
Total N ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Genomic instability is a driving force in tumor development that can be achieved by a variety of mechanisms, such as defective chromosome segregation or inactivation of the DNA mismatch repair pathway. Although B-cell lymphomas are associated with chromosomal translocations deregulating oncogene expression, a mechanism for genome-wide instability during lymphomagenesis has long not been described. We have reported that the somatic hypermutation process (SHM), which normally targets the immunoglobulin variable region (IgV) and BCL6 genes in germinal center (GC) B-cells, functions aberrantly in >50% of diffuse large B-cell lymphoma (DLBCL), the most common type of B-cell non-Hodgkin lymphoma (Pasqualucci et al., Nature412:341, 2001). As a consequence, multiple somatic mutations are introduced into the 5′ region of genes that do not represent physiologic SHM targets, including known proto-oncogenes such as PIM1, PAX5, RhoH/TTF and cMYC. To further define the extent of this phenomenon, termed aberrant somatic hypermutation (ASHM), and to identify additional hypermutated loci of possible pathogenetic significance in DLBCL, we screened 113 genes for the presence of mutations affecting their 5′ sequences (≥1.3 Kb from the transcription start site, the target region for SHM) in 10 DLBCL cell lines. Fifteen genes (13.3%) were found to harbor a significant number of mutations (p<0.05), with 70% of the cell lines being mutated in 7 or more genes; among these, six B-cell specific loci -BCL7A, CIITA, IRF4, LRMP, NCOA3 and SIAT1- carried 9–53 mutational events distributed in 20 to 70% of the cases, corresponding to an overall mutation frequency of 0.032–0.15% (frequency in the mutated cases: 0.07–0.25%). The same genes were found hypermutated in a panel of 20 primary DLBCL biopsies, which displayed an overall mutation load of 7 to 45 distinct events/gene (total N=125). Mutations were of somatic origin, independent of chromosomal translocations to the Ig loci and were restricted to the first 1.5–2 Kb from the promoter. In addition, analogous to previously identified SHM and ASHM targets, the mutations exhibited characteristic features, including a bias for transitions over transversions, preferential hotspot (RGYW/WRCY motifs) targeting, and higher frequencies at G:C pairs. However, in contrast to physiologic SHM targets such as IgV and BCL6, none of the 4 newly identified hypermutated genes that have been analyzed so far (BCL7A, CIITA, SIAT1, LRMP) displayed significant levels of mutations in purified normal GC B-cells as well as in other B-cell malignancies. This finding indicates that these genes represent aberrant hypermutation targets resulting from a tumor-associated malfunction, possibly a loss of target specificity of the physiologic SHM process. Considering previous results and the present survey, 17 (13%) out of 130 genes investigated have been found involved in ASHM, suggesting that this aberrant activity may involve an extensive set of target genes in DLBCL. Since the mutations affect both regulatory and coding sequences of the targeted genes, aberrant SHM may represent a major contributor to the pathogenesis of this disease and may explain in part its phenotypic and clinical heterogeneity.

Colonic Marginal Zone B-Cell Lymphoma (MALT Lymphoma) in a Patient Negative for H. pylori: Case Report

2018 ◽  
Vol 113 (Supplement) ◽  
pp. S937-S938
Author(s):  
Gurjiwan S. Virk ◽  
Jennifer Copare ◽  
Sven Hida ◽  
Seth J. Richter
Keyword(s):  
Case Report ◽  
B Cell ◽  
Malt Lymphoma ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
H Pylori

scholarly journals Molecular Pathogenesis of MALT Lymphoma

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Katharina Troppan ◽  
Kerstin Wenzl ◽  
Peter Neumeister ◽  
Alexander Deutsch
Keyword(s):  
Malt Lymphoma ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Molecular Pathogenesis ◽  
Chromosomal Translocations ◽  
Chronic Infections ◽  
Genetic Abnormalities ◽  
Wide Range ◽  
Genetic Aberration

Approximately 8% of all non-Hodgkin lymphomas are extranodal marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT), also known as MALT lymphoma, which was first described in 1983 by Isaacson and Wright. MALT lymphomas arise at a wide range of different extranodal sites, with the highest frequency in the stomach, followed by lung, ocular adnexa, and thyroid, and with a low percentage in the small intestine. Interestingly, at least 3 different, apparently site-specific, chromosomal translocations and missense and frameshift mutations, all pathway-related genes affecting the NF-κB signal, have been implicated in the development and progression of MALT lymphoma. However, these genetic abnormalities alone are not sufficient for malignant transformation. There is now increasing evidence suggesting that the oncogenic product of translocation cooperates with immunological stimulation in oncogenesis, that is, the association with chronic bacterial infection or autoaggressive process. This review mainly discusses MALT lymphomas in terms of their genetic aberration and association with chronic infections and summarizes recent advances in their molecular pathogenesis.

scholarly journals Incidentally Discovered Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue in the Colon

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Raja Chandra Chakinala ◽  
Khwaja F. Haq ◽  
Jonathan E. Barsa ◽  
Shantanu Solanki ◽  
Lavneet Chawla ◽  
...  
Keyword(s):  
B Cell ◽  
Malt Lymphoma ◽  
Lymphoid Tissue ◽  
Colonic Mucosa ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Occult Blood ◽  
Fecal Occult Blood ◽  
Fecal Occult

We present a case of colonic mucosa-associated lymphoid tissue (MALT) lymphoma in a 62-year-old woman diagnosed after a positive test for fecal occult blood.

A Newly Identified Translocation t(X;14)(p11;q32) In MALT Lymphoma Involving IGHS and GPR34 Reveals A Novel Role for GPR34 In Cell Growth and Tumor Development

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1999-1999
Author(s):  
Stephen M. Ansell ◽  
Takashi Akasaka ◽  
Michelle Manske ◽  
Tammy Price-troska ◽  
Steven Ziesmer ◽  
...  
Keyword(s):  
Cell Growth ◽  
B Cell ◽  
Vector Control ◽  
Mrna Expression ◽  
Malt Lymphoma ◽  
Research Funding ◽  
Marginal Zone ◽  
Luciferase Activity ◽  
Cell Lymphoma ◽  
B Cell Lymphoma

Abstract Abstract 1999 Recurrent chromosomal translocations involving the IGH locus are characteristic of B-cell non-Hodgkin lymphoma (NHL) and MALT lymphoma in particular has been pathologically characterized by specific IGH translocations. However, these translocations are present in only a subset of cases, suggesting that additional uncharacterized translocations might exist. In previous studies we characterized the novel t(X;14)(p11.4;q32) translocation in a patient with MALT lymphoma and found that GPR34, an orphan G-protein coupled receptor (GPCR), was highly expressed due to its juxtaposition to the IGHSA2 switch region. Although the t(X;14)(p11;q32) translocation was only identified in one patient, we wanted to determine its expression across a spectrum or normal and malignant lymphoma tissue, as other mechanisms may contribute to overexpression of genes. We measured GPR34 mRNA expression by quantitative PCR in tissue biopsies from a panel of lymphomas. As controls, we also measured GPR34 mRNA expression in normal resting or activated CD19+ B cells, resting and activated CD3+ T cells, and CD14+ monocytes. Expression of GPR34 was significantly increased in MALT (37-fold, n=35), LPL (23-fold, n=23), nodal marginal zone B cell lymphoma (18-fold, n=21), and splenic marginal zone B cell lymphoma (21 fold, n=33) compared to resting CD19+ B cells (n=11). In a gastric MALT lymphoma specimen we detected GPR34 expression at levels similar to the t(X;14)(p11;q32) patient and interphase FISH studies showed an extra intact GPR34 signal, but no translocation involving IGH or GPR34, suggesting that other mechanisms, including gene dosage effect, can upregulate GPR34. The receptor encoded by GPR34 is most similar to the PY2 receptor subfamily of GPCRs and signaling studies suggest that overexpression of GPR34 results in an accumulation of inositol phosphates and MAP-kinase activation. To further characterize the impact of GPR34 overexpression on cell signaling, HeLa cells were transduced with WT GPR34, a signaling deficient GPR34 (GPR34 DRY), or a vector control. To determine if MAPK activity was upregulated, the phosphorylation status of ERK1/2 in GPR34 WT, GPR34 DRY, and vector control cells was analyzed and we found that ERK1/2 was constitutively phosphorylated at higher levels (1.6-fold) in GRP34 WT cells compared to GRR34 DRY or vector control cells. To further explore which signaling pathways were affected by GPR34 overexpression, GPR34 WT or vector control cells were transfected with an AP-1, CRE, NF-kB, E2F, SRE, NFAT, or ISRE- luciferase reporter plasmid. GPR34 expressing cells had increased luciferase activity driven by AP-1 (5.35-fold), CRE (4.7-fold), NF-kB (2.6-fold), and E2F (2.1) when compared to vector control cells. GPR34 DRY was unable to activate these pathways. AP-1 and CRE have been implicated in a large variety of cellular processes, including transformation, and both AP-1 and CRE activity is induced upon activation of MAP kinases. In untreated cells, both AP-1 and CRE activity were significantly higher in GPR34 WT cells compared to GPR34 DRY cells and both AP-1 and CRE luciferase activity was inhibited by the MEK1 inhibitor PD98059, suggesting that activation of these pathways is MAP-kinase dependent. To determine the biologic impact of GRP34 overexpression, the proliferation rates of vector control, GPR34 WT, and GPR34 DRY cells were compared and we found that proliferation of GPR34 WT cells was significantly higher (5.6-fold) than that seen in GPR34 DRY cells. We next tested the effect of the MEK inhibitor on proliferation and saw a dose dependent decrease in proliferation of GPR34 WT expressing cells. These results suggest that GPR34-mediated proliferation is dependent on MAPK. The presence of elevated GPR34 expression in tumors and the increased proliferation mediated by GPR34 suggests that it may have oncogenic potential. We therefore tested the ability of GPR34 WT cells to generate tumors in a tumor colony-forming assay. Only the GRP34 WT cells had the ability to form tumors in soft agar suggesting that overexpression of GPR34 can result in tumor formation. Taken together, our results identify a novel translocation in MALT lymphoma, emphasize a novel role for GPR34 in tumor cell growth, and suggest that MEK inhibitors may be useful in a subset of translocation-harboring or GRP34 high-expressing tumors. Disclosures: Fonseca: Genzyme: Consultancy; Medtronic: Consultancy; BMS: Consultancy; AMGEN: Consultancy; Otsuka: Consultancy; Celgene: Consultancy, Research Funding; Intellikine: Consultancy; Cylene: Research Funding; Onyx: Research Funding; FISH probes prognostication in myeloma: Patents & Royalties.

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