Splenic Marginal Zone Lymphoma with Villous Lymphocytes Shows On-Going Immunoglobulin Gene Mutations

Tierens, Anne; Delabie, Jan; Małecka, Agnieszka; Wang, Junbai; Gruszka-Westwood, Alicja M.; Catovsky, Daniel; Matutes, Estella

doi:10.1016/s0002-9440(10)63862-x

Cited by 43 publications

(41 citation statements)

References 48 publications

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“…4a). This is in agreements with previous studies where similarities to both memory B-cells [34] and splenic marginal zone B-cells [70][71][72][73] has been observed. The cause of the distinct gene expression profile of HCL cells could be either due to an onset of a unique signaling pathways compared with the other BCLs which is indicated by the high expression of MAF suggested to change the expression profile toward a myeloid differentiation [35,36], or a distinct cell of origin, potentially a splenic B-cell, which remains to be determined.…”

Section: Discussionsupporting

confidence: 93%

Identification of uniquely expressed transcription factors in highly purified B‐cell lymphoma samples

et al. 2010

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Transcription factors (TFs) are critical for B-cell differentiation, affecting gene expression both by repression and transcriptional activation. Still, this information is not used for classification of B-cell lymphomas (BCLs). Traditionally, BCLs are diagnosed based on a phenotypic resemblance to normal B-cells; assessed by immunohistochemistry or flow cytometry, by using a handful of phenotypic markers. In the last decade, diagnostic and prognostic evaluation has been facilitated by global gene expression profiling (GEP), providing a new powerful means for the classification, prediction of survival, and response to treatment of lymphomas. However, most GEP studies have typically been performed on whole tissue samples, containing varying degrees of tumor cell content, which results in uncertainties in data analysis. In this study, global GEP analyses were performed on highly purified, flow-cytometry sorted tumor-cells from eight subgroups of BCLs. This enabled identification of TFs that can be uniquely associated to the tumor cells of chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hairy cell leukemia (HCL), and mantle cell lymphoma (MCL). The identified transcription factors influence both the global and specific gene expression of the BCLs and have possible implications for diagnosis and treatment. Am. J. Hematol. 85:418-425, 2010. V

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Section: Discussionsupporting

confidence: 93%

Identification of uniquely expressed transcription factors in highly purified B‐cell lymphoma samples

et al. 2010

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“…7,8 Previous studies by us and others have shown that SMZL shows a biased IG gene repertoire and is characterized by heterogeneity with regard to the mutational status of the IG receptors. 4,9 --23 Individual studies have highlighted different IG sequence features, including repertoire differences between SMZL, SDRL and hairy cell leukemia-variant; 4,15 intraclonal diversification of IG genes through ongoing SHM; 12,17,18,23 potential analogies between SMZL and hairy cell leukemia-variant; 15 and, very recently, the existence of cases sharing quasi-identical antigen-binding sites (stereotyped B-cell receptors). 21 Furthermore, some studies have also examined whether particular molecular characteristics of the IG receptors might be associated with genetic or phenotypic features, and/or clinical outcome.…”

Section: Introductionmentioning

confidence: 99%

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

et al. 2012

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We performed an immunogenetic analysis of 345 IGHV --IGHD --IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; 12.8%; 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele *04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2*04 peaked at 31%. The IGHV1-2*04 rearrangements carried significantly longer complementaritydetermining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2*04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97 --99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2*04 allele.

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“…In contrast to other B-cell lymphomas, no consistent or unique genetic lesion has been associated with SMZL. Furthermore, there is abundant cytogenetic and molecular evidence pointing to SMZL genetic heterogeneity and the existence of distinct subentities: with/without plasma cell differentiation, IG and BCL-6 somatic mutations (9)(10)(11)(12)(13)(14)(15), allelic loss at chromosome 7q21-32 (16), and hepatitis C infection (17).…”

Section: Introductionmentioning

confidence: 99%

“…Important information pertaining to these issues can be provided by analysis of clonogenic IG gene mutations, which generally helps to trace the developmental stage at which neoplastic transformation had occurred and assign the neoplastic cells to their corresponding normal counterparts. In SMZL, the available data derive exclusively from analysis of IGH genes (mostly in small groups of patients [9-10, 12-13,15, with only 2 comprehensive series; 11,14]). These studies have provided evidence for the significant heterogeneity of SMZL with respect to IGH mutation load.…”

Section: Introductionmentioning

confidence: 99%

Immunoglobulin Heavy- And Light-chain Repertoire in Splenic Marginal Zone Lymphoma

Stamatopoulos

Belessi

Papadaki

et al. 2004

Mol Med

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The considerable heterogeneity in morphology, immunophenotype, genotype, and clinical behavior of splenic marginal zone lymphoma (SMZL) hinders firm conclusions on the origin and differentiation stage of the neoplastic cells. Immunoglobulin (IG) gene usage and somatic mutation patterns were studied in a series of 43 SMZL cases. Clonal IGHV-D-J rearrangements were amplified in 42/43 cases (4 cases carried double rearrangements). Among IGHV-D-J rearrangements, IGHV3 and IGHV4 subgroup genes were used with the highest frequency. Nineteen IGHV genes were unmutated (>98% homology to the closest germline IGHV gene), whereas 27/46 were mutated. Clonal IGKV-J and IGLV-J gene rearrangements were amplified in 36/43 cases, including 31 IGKV-J (8/31 in lambda light-chain expressing cases) and 12 IGLV-J rearrangements; 9/31 IGKV and 6/12 IGLV sequences were mutated. IGKV-J and IGLV-J rearrangements used 14 IGKV and 9 IGLV different germline genes. Significant evidence for positive selection by classical T-dependent antigen was found in only 5/27 IGHV and 6/15 IGKV+IGLV mutated genes. These results provide evidence for the diverse B-cell subpopulations residing in the SMZ, which could represent physiologic equivalents of distinct SMZL subtypes. Furthermore, they indicate that in SMZL, as in other B cell malignancies, a complementarity imprint of antigen selection might be witnessed either by IGHV, IGKV, or IGLV rearranged sequences.

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Splenic Marginal Zone Lymphoma with Villous Lymphocytes Shows On-Going Immunoglobulin Gene Mutations

Abstract: Splenic marginal zone lymphoma (also splenic lymphoma with villous lymphocytes) is a B-cell non-

Cited by 43 publications

References 48 publications

Identification of uniquely expressed transcription factors in highly purified B‐cell lymphoma samples

Identification of uniquely expressed transcription factors in highly purified B‐cell lymphoma samples

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

Immunoglobulin Heavy- And Light-chain Repertoire in Splenic Marginal Zone Lymphoma

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