Cellular Origin of Human B-Cell Lymphomas

Küppers, Ralf; Klein, Ulf; Hansmann, Martin‐Leo; Rajewsky, Klaus

doi:10.1056/nejm199911113412007

Cited by 635 publications

(534 citation statements)

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“…The majority of our gastric MALT lymphomas showed somatic mutation, which is consistent with a derivation from postgerminal center memory B cells. 33,34 In conclusion, we showed that inflammationdependent gastric MALT lymphomas frequently used particular VH fragments and that this usage was not found in inflammation-independent tumors. This finding suggests that the former tumors may be derived from a highly restricted, probably H. pyloriassociated, B cell subset and that tumor progression from the former to the latter may not commonly occur.…”

Section: Discussionmentioning

confidence: 68%

Immunoglobulin VH gene analysis in gastric MALT lymphomas

et al. 2007

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The majority of gastric mucosa-associated lymphoid tissue (MALT) lymphomas are successfully treated with Helicobacter pylori eradication alone. However, certain subsets of these tumors are resistant to the eradication treatment. As API2-MALT1 fusion is a feature of one of these subsets, we divided gastric MALT lymphomas into three groups: eradication-responsive and API2-MALT1 fusion-negative (Group A), eradication-resistant and fusion-negative (Group B), and eradication-resistant and fusion-positive (Group C). To characterize further gastric MALT lymphomas, we analyzed VH genes, which do not change in the course of tumor progression, by extensive subcloning of the monoclonal PCR products of 45 cases. VH3-23 and VH3-30 were preferentially used in Group A tumors (14/23 cases, 61%) as compared with Group B (1/10 cases, 10%, P ¼ 0.0094) and Group C (2/ 12 cases, 17%, P ¼ 0.017). Tumors of Groups B and C used variegated VH fragments, and no dominant VH fragments were noted. Somatic mutation was detected in most of the cases. Ongoing mutation was detected in 3/45 cases (7%), when assessed according to strict criteria for a confirmed mutation. These findings suggest that inflammation-dependent tumors (Group A) may be derived from a highly restricted, probably H. pyloriassociated, B cell subset and may not often progress to those that are inflammation-independent (Groups B and C). Although considered to be common in this tumor, ongoing mutation may be infrequent when assessed by strict criteria. Keywords: gastric MALT lymphoma; helicobacter pylori; eradication; immunoglobulin heavy chain variable genes; API2-MALT1 fusion gene Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) is a distinct low-grade lymphoma, which is typically localized long term at the site of origin. 1 A preexisting chronic inflammation, such as Helicobacter pylori gastritis, Hashimoto's thyroiditis, or Sjogren's syndrome is considered to influence significantly its development. 1 The etiological link between gastric MALT lymphoma and H. pylori gastritis has arisen from the fact that the majority of gastric MALT lymphomas (approximately 70% of cases) show complete regression on eradication of H. pylori alone. 2 API2-MALT1 fusion, cloned from t(11;18)(q21;q21), is a gene alteration specific to MALT lymphomas. 3,4 API2 is a member of the IAP (inhibitor of apoptosis) gene family, and is essential for the suppression of apoptosis. 5 MALT1, a novel

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Section: Discussionmentioning

confidence: 68%

Immunoglobulin VH gene analysis in gastric MALT lymphomas

et al. 2007

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“…** Recent studies have demonstrated that there are 2 subtypes of CLL: one derives from pre-GC B-cell and the other from post-GC memory B-cells (9,10). *** IgH gene rearrangement is associated with TcR-␥ gene rearrangement in these cases.…”

Section: Patients and Specimens Studiedmentioning

confidence: 99%

“…2 and 3). As shown in Table 1, in precursor B-lymphoblastic leukemia/lymphoma, in chronic lymphocytic leukemia, and in mantle cell lymphoma, cases that usually lack mutations in the V H gene segments, the detection rate of clonally rearranged IgH genes was nearly 100% (10). In this group of lymphomas, the three sets of primers, used in this study for IgH gene rearrangement analysis, were usually all positive, indicating the unmutated status of the V H segments in these cases (4).…”

Section: Igh-chain and Tcr-␥ Gene Rearrangement Studies Of B-cell Andmentioning

confidence: 99%

“…Thus, tumors derived from naive lymphocytes, also designated pre-germinal center (pre-GC) naive B cells, express unmutated V Hregion genes and show a high detection rate of clonal IgH gene rearrangement by polymerase chain reaction (PCR). In this category are precursor B-lymphoblastic leukemia/lymphoma, mantle cell lymphoma, and a subset of chronic lymphocytic leukemia (9,10). The other group of tumors derived from memory B cell, generated in the GC and characterized by cells bearing somatically hypermu-tated V H -region genes (GC and post-GC memory B cells), give a lower rate of clonality by PCR methodology.…”

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confidence: 99%

“…The other group of tumors derived from memory B cell, generated in the GC and characterized by cells bearing somatically hypermu-tated V H -region genes (GC and post-GC memory B cells), give a lower rate of clonality by PCR methodology. In the latter group are the majority of non-Hodgkin's B-cell lymphoma subtypes such as lymphoplasmacytic, mucosa-associated lymphoid tissue (MALT) type, follicle-center lymphomas, hairy cell leukemia, diffuse large-cell lymphomas, Burkitt's lymphomas, multiple myeloma, and some chronic lymphocytic leukemias (9,10). In these latter cases, the mutations at binding sites of the primers account for the lower amplification rate of IgH gene rearrangements (4).…”

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PCR Analysis of Immunoglobulin Heavy Chain (IgH) and TcR-γ Chain Gene Rearrangements in the Diagnosis of Lymphoproliferative Disorders: Results of a Study of 525 Cases

et al. 2000

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This report summarizes a cumulative 4-year experience in polymerase chain reaction (PCR) analysis of immunoglobin heavy chain (IgH) and TcR-␥ chain gene rearrangements in 525 cases of lymphoproliferative disorders. Because the sensitivity of the PCR methodology was found to be tissue dependent, in the study of the presence of clonal cell population in tissues containing a small number of polyclonal lymphocytes, such as skin and gastrointestinal biopsy specimens, we used the multiple-PCR run approach. In this latter methodology, we repeat the PCR reaction from the same sample at least three times to confirm the reproducibility of the results. In the study of 273 cases of B-or T-cell lymphomas with characteristic immunomorphological and clinical features, a clonal IgH or TcR-␥ chain gene rearrangement was detected in approximately 80% of cases. A clonal rearrangement involving both IgH and TcR-␥ chain genes was found in 10% of cases of both B-cell and T-cell lymphomas. The study of 167 cases of nonneoplastic lymphoid tissue samples showed the presence of clonally rearranged cell populations for IgH or TcR-␥ genes in 3 and 9% of cases, respectively. We also applied PCR for the study of 85 cases of lymphoproliferations with no definite diagnosis (i.e., benign versus malignant) after immunomorphological analysis. In 65 cases (76%), the correlation of immunomorphological features with the presence (48 cases) or the absence (17 cases) of clonal lymphoid cell populations led to a definite diagnosis. In almost all these cases, the final diagnosis was found to be in agreement with the clinical course. In the 20 remaining cases (24%), no definite diagnosis could be made. We also assessed the value of PCR in detecting bcl-2/J H gene rearrangement as an additional clonal marker in the diagnosis of follicular lymphoma. Bcl-2/J H rearrangement and/or IgH gene rearrangement was found in approximately 85% (71/85) of follicular lymphoma cases studied.

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Somatic Hypermutation

K��ppers¹,

Goossens²

2002

Wiley Encyclopedia of Molecular Medicine

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Cellular Origin of Human B-Cell Lymphomas

Cited by 635 publications

References 82 publications

Immunoglobulin VH gene analysis in gastric MALT lymphomas

Immunoglobulin VH gene analysis in gastric MALT lymphomas

PCR Analysis of Immunoglobulin Heavy Chain (IgH) and TcR-γ Chain Gene Rearrangements in the Diagnosis of Lymphoproliferative Disorders: Results of a Study of 525 Cases

Somatic Hypermutation

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