Kooperativer Bibliotheksverbund

In: Bioinformatics, Oxford University Press (OUP), Vol. 33, No. 3 ( 2017-02-01), p. 435-437

Abstract: The study of immunoglobulins and T cell receptors using next-generation sequencing has finally allowed exploring immune repertoires and responses in their immense variability and complexity. Unsurprisingly, their analysis and interpretation is a highly convoluted task. Results We thus implemented ARResT/Interrogate, a web-based, interactive application. It can organize and filter large amounts of immunogenetic data by numerous criteria, calculate several relevant statistics, and present results in the form of multiple interconnected visualizations. Availability and Implementation ARResT/Interrogate is implemented primarily in R, and is freely available at http://bat.infspire.org/arrest/interrogate/ Supplementary information Supplementary data are available at Bioinformatics online.

Type of Medium: Online Resource

ISSN: 1367-4803 , 1367-4811

URL: Article

DOI: 10.1093/bioinformatics/btw634

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2017

detail.hit.zdb_id: 1468345-3

SSG: 12

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1464-1464

Abstract: Hepatitis C virus (HCV) infection is a well-established risk factor for the development of B cell non-Hodgkin lymphoma (B-NHL). Two main pathways have been proposed to explain the role of the virus in lymphomagenesis: 1) transformation of B cells either directly by oncogenic viral proteins, or by a hit-and-run mechanism inducing a mutator phenotype, and 2) chronic antigenic stimulation through the B cell receptor (BcR) in conjunction to the binding of the viral E2 protein to its receptor CD81. There are however conflicting data regarding whether the BcR of the lymphomatous cells are capable of directly recognizing viral proteins or, rather, they possess a rheumatoid factor (RF) activity, binding instead polyclonal immunoglobulin (IG) within immune complexes trapping the virus. To further elucidate the role of antigenic stimulation in the natural history of HCV-associated B-NHL, we analyzed the IG gene repertoire of both heavy and light chains expressed by neoplastic cells in 41 cases of HCV-associated NHL, including: 29 marginal zone lymphoma (MZL); 7 diffuse large B-cell lymphoma (DLBCL) of which 3 originated from transformed MZL ; and 5 other low-grade B-cell NHL. Tumor cells were obtained from blood in 39 cases, bone marrow and a lymph node biopsy in 1 case each. Forty-three productive IGHV-IGHD-IGHJ gene rearrangements were obtained, which displayed a clear biased gene composition as 3 IGHV genes contributed to almost half of the repertoire: IGHV1-69 (11/43, 25,6%), IGHV3-7 (5/43, 11.6%), IGHV3-21 (4/43, 9.3%). This was also true for both IGHD genes (IGHD3-22: 12/43, 27.9%), and IGHJ genes (IGHJ4: 17/43, 39.5%; IGHJ3: 17/43, 25.6%). All but 3 sequences carried somatic hypermutations (SHM) in their IGHV genes with a median identity to the germline of 97.6% (range 86.5-100%). Thirty-eight productive IG light chain rearrangement sequences were obtained from 36 cases, of which 30 (78.9%) were IGK. Similarly, they exhibited strong gene usage bias with an over-representation of IGKV3-20 (9/30, 30%), as well as IGKJ1 (11/30, 33.3%) and IGKJ2 (6/30, 20%). IG light chain sequences were found to harbor similar SHM load with a 97% median identity to germline (range 91-100%). As previously described, we observed preferential pairing of heavy and light chain genes, with 6 of the 9 IGHV1-69 cases (with available light chain sequence data) being associated with IGKV3-20. Using established criteria, we found 5 cases (11.6%) carrying stereotyped BcR i.e. IGHV-IGHD-IGHJ gene rearrangements with quasi-identical amino-acid (AA) sequences, including the highly variable complementary determining region 3 (CDR3). Three cases concerned IGHV3-7/IGHD3-22/IGHJ3 rearrangements with an 18 AA-long CDR3, and 2 concerned IGHV1-69/IGHD3-22/IGHJ4 rearrangements with a 13 AA-long CDR3. Identity within the CDR3 extended to AA encoded by randomly inserted N-region nucleotides. We failed to establish correlations between histological categories and IG repertoire, probably due to the uneven distribution of lymphoma subtypes within our cohort. In contrast, most if not all sequences with biased IG gene usage, including the 5 stereotyped BcR ones, were found amongst the 28/41 cases (68.3%) with mixed cryoglobulinemia type II and/or positive for RF (MC/RF+). These two categories of patients differed also regarding the SHM load of their IGHV genes since MC/RF+ cases were signlificantly less mutated than MC/RF- cases (median identity to germline: 97.9% vs 95.9%, p= 0.048). We then searched for similar sequences in public databases and collaborative studies. Stereotyped BcR sequences similar to those of our cases were detected in HCV-associated lymphoma, but also in other HCV-negative B-cell maligancies e.g. MALT lymphoma (some associated with RF) and chronic lymphocytic leukemia, non malignant B cells with RF activity, and non malignant marginal zone splenic B cells. Sequence similarity extended to some shared AA replacements, e.g. identical AA introduced by HSM at the same positions. In conclusion we confirm the highly biased IG repertoire of HCV-associated lymphoma. However this feature seems to be linked essentially to the presence of a MC and/or RF. As quasi-identical sequences are found in HCV-negative malignant and normal B cells, our data support the hypothesis that HCV-associated lymphomatous cells originate from precursors endowed with auto-immune properties rather than B cells expressing an anti-virus BcR. Disclosures Stamatopoulos: Gilead Sciences: Research Funding; Janssen Pharmaceuticals: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1464.1464

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Molecular Immunology, Elsevier BV, Vol. 60, No. 1 ( 2014-07), p. 54-61

Type of Medium: Online Resource

ISSN: 0161-5890

URL: Article

DOI: 10.1016/j.molimm.2014.03.009

Language: English

Publisher: Elsevier BV

Publication Date: 2014

detail.hit.zdb_id: 2013448-4

SSG: 12

In: Molecular Medicine, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2013-01), p. 332-332

Abstract: Eugenia Tsakou, Andreas Agathagelidis, Myriam Boudjoghra, Thorsten Raff, Antonis Dagklis, Maria Chatzouli, Tatjana Smilevska, George Bourikas, Helene Merle-Beral, Eleni Manioudaki-Kavallieratou, Achilles Anagnostopoulos, Monika Bru.ggemann, Frederic Davi, Kostas Stamatopoulos, and Chrysoula Belessi. (2012) Partial versus Productive Immunoglobulin Heavy Locus Rearrangements in Chronic Lymphocytic Leukemia: Implications for B-Cell Receptor Stereotypy. Mol. Med. 2012 Feb 10;18:138–45.

Type of Medium: Online Resource

ISSN: 1076-1551 , 1528-3658

URL: Article

DOI: 10.2119/molmed.2011.00216.erratum

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2013

detail.hit.zdb_id: 1475577-4

detail.hit.zdb_id: 1283676-X

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2346-2346

Abstract: Abstract 2346 Poster Board II-323 A strong sequence-based evidence supporting a role for antigen in the development of CLL is the existence of subsets of patients with stereotyped heavy complementarity-determining region 3 (HCDR3) sequences. Stereotyped HCDR3s are often defined by the selective association of certain IGHD genes in specific reading frames (RF) with certain IGHJ genes, especially IGHJ6. To gain insight into the mechanisms shaping the IG repertoire and also determine the developmental stage when restrictions in HCDR3 are imposed, we investigated the molecular features of incomplete IGHD-IGHJ rearrangements (IDJR) in a series of 830 patients with CLL. IDJRs were detected in 272/830 cases (32.7%). No associations were identified between the occurrence of IDJRs and IGHV gene usage or mutational status in the complete IGHV-D-J rearrangement from the coding IGH allele. A trend for higher IDJR frequency was evident, however, in certain subsets with stereotyped HCDR3s, in particular subset #1 (IGHV1-5-7/IGHD6-19/IGHJ4; 13/33 cases, 40%), #7 (IGHV1-69/IGHD3-3/IGHJ6; 10/21 cases, 48%) and #8 (IGHV4-39/IGHD6-13/IGHJ5; 5/12 cases, 41%). Sequence analysis of the IDJRs revealed: (i) increased frequency of IGHD2 subgroup genes (115/238 cases, 48%), especially IGHD2-2; (ii) equal distribution of the three RFs of the IGHD genes; (iii) increased recombination frequency between 5`genes of the IGHD cluster and 3` genes of the IGHJ cluster, suggestive of secondary rearrangements on the same allele. Overall, 205/238 (86%) IDJRs were considered as potentially functional (PF), since they did not carry a stop codon at the IGHD-J junction. Of note, 26/28 (93%) IDJRs detected in cases from subsets #1, 7 and 8 could be assigned to the PF category. In the group of CLL cases carrying PF IDJRs, comparison of the IGHD gene repertoire in IDJRs vs. complete, expressed IGHV-D-J rearrangements (CE-VDJRs) revealed: (i) statistically significant (p 〈 0.001) selection of the IGHD3-3 and IGHD6-19 genes in RF2 and RF3, respectively, among CE-VDJRs (especially those assigned to subsets #7 and #1, respectively); (ii) preferential usage of RFs encoding for hydrophilic peptides among CE-VDJRs. At a subsequent stage, we compared the repertoire of the IDJRs from the CLL cohort to that of 174 IDJRs obtained from patients with pre-B acute lymphoblastic leukemia (ALL). Except for higher frequency of (i) the IGHD7-27 and IGHJ6 genes and (ii) IGHD-IGHD gene fusions in pre-B ALL, the overall configuration of IDJRs did not differ significantly in CLL vs. pre-B ALL. In conclusion, these results document that the early stages of IG gene rearrangements in pre-B ALL and CLL do not show intrinsic, disease-specific differences. The detailed molecular characterization and comparison of the IGHD and IGHJ gene repertoires in IDJRs vs. CE-VDJRs in CLL provides further support for the notion that CLL development is not stochastic but directed by selection operating at the IG protein level. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.2346.2346

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4376-4376

Abstract: The existence of stereotyped B cell receptor immunoglobulins (BcR IG) in chronic lymphocytic leukemia (CLL) strongly implicated antigen selection in disease ontogeny. We have previously shown that the stereotyped fraction encompasses ~30% of all CLL and includes multiple subsets with distinct BcR IG configuration and variable size. Eventually, certain major subsets emerged as distinct clinical entities, exemplified by subset #2 (IGHV3-21/IGLV3-21, ~2.5-3% of all CLL, mixed somatic hypermutation (SHM) status) of a particularly aggressive clinical course, thus, sharply contrasting subset #4 (IGHV4-34/IGKV2-30, ~1% of all CLL, mutated IGHV genes, M-CLL), a prototype for indolent disease. Here, taking advantage of a multi-institutional cohort of 21,123 CLL IG rearrangements, almost three times the size of the largest previous study, and the availability of validated, purpose-built immunoinformatics methods, we reappraised BcR IG stereotypy especially focusing on major subsets and the degree of their sequence similarity to related minor subsets. Stereotypy discovery was performed with ARResT/Teiresias, while stereotypy assignment to existing subsets previously deemed as major was performed with ARResT/AssignSubsets (http://bat.infspire.org/arrest/). In the present study, a subset was characterized as major if representing 〉 0.2% of the cohort (i.e. at least 50 cases). Minor subsets closely related to major ones (termed satellite) were identified applying the following criteria: (i) usage of IGHV genes from the same phylogenetic clan; (ii) VH CDR3 length difference ranging from -2 to +2 compared to the respective major subset; (iii) shared VH CDR3 sequence motif; and, (iv) -2 to +2 difference in the offset of the VH CDR3 motif compared to the respective major subset. In total, 7378/21123 (34.9%) IG sequences were grouped into subsets with stereotyped VH CDR3, with the previously characterized 19 major subsets accounting collectively for 2594 sequences (12.3%) of the cohort: of these, 12 included cases with unmutated IGHV genes (U-CLL), 6 concerned M-CLL and 1 (subset #2) included cases with mixed SHM status. Four additional subsets exceeded 50 cases, and, thus, were also considered as 'major'. These results reinforce the notion that not all CLL will end up being stereotyped but rather that a plateau for stereotypy exists at ~1/3 of the cohort. Subset #2 was the largest subset (n=572, 2.7%), while subset #1 (IGHV clan I (IGHV1,5,7 subgroups)/IGKV1(D)-39) was the most frequent subset within U-CLL (n=515, 2.4%) and subset #4 the most common M-CLL subset (n=192, 0.9%), hence displaying remarkable consistency regarding their frequency in all cohorts published since the pioneering studies. Altogether, Teiresias and AssignSubsets gave concordant results for previously identified major subsets, illustrating the validity of our approach. Satellite subsets were sought for individually for each major subset. In general, few satellite subsets were identified, most of which concerned U-CLL major subsets. That notwithstanding, notable cases of satellite subsets were exemplified by major subset #1 and its satellite subset #99 from which it differed only in VH CDR3 length (13 aminoacids in subset #1 versus 14 in subset #99); interestingly, both subsets displayed equally aggressive clinical course. Another example concerned subset #8 (IGHV4-39/IGKV1(D)-39, U-CLL), an aggressive subset with very high risk for Richter's transformation, that, except for a one-aminoacid difference in VH CDR3 length, was otherwise identical to satellite subset #215, also displaying clinical aggressiveness. Overall, our results confirm that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease subgroups amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Most major subsets display unique sequence motifs, however satellite subsets exist, especially within U-CLL. Considering ever-increasing evidence that major stereotyped subsets may represent distinct disease subgroups, the existence of satellite subsets reveals a novel aspect of repertoire restriction and has implications for refined molecular classification of CLL. Disclosures Shanafelt: Genentech: Research Funding; GlaxoSmithkKine: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Cephalon: Research Funding; Hospira: Research Funding. Gaidano:Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Niemann:Janssen: Consultancy; Abbvie: Consultancy; Roche: Consultancy; Gilead: Consultancy. Langerak:F. Hofmann-LaRoche, Genentech: Research Funding; InVivoScribe Technologies: Patents & Royalties: Royalties are provided to European Network (EuroClonality). Jaeger:Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kater:Celgene: Research Funding; Gilead: Research Funding; Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Stilgenbauer:Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding. Hallek:Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Rosenquist:Gilead Sciences: Speakers Bureau. Ghia:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding; Adaptive: Consultancy; Abbvie: Consultancy, Honoraria. Stamatopoulos:Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses, Research Funding; Gilead: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.4376.4376

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Advances, American Society of Hematology, Vol. 4, No. 7 ( 2020-04-14), p. 1357-1366

Abstract: Primary vitreoretinal lymphoma (PVRL) is a high-grade lymphoma affecting the vitreous and/or the retina. The vast majority of cases are histopathologically classified as diffuse large B-cell lymphoma (DLBCL) and considered a subtype of primary central nervous system lymphoma (PCNSL). To obtain more insight into the ontogenetic relationship between PVRL and PCNSL, we adopted an immunogenetic perspective and explored the respective immunoglobulin gene repertoire profiles from 55 PVRL cases and 48 PCNSL cases. In addition, considering that both entities are predominantly related to activated B-cell (ABC) DLBCL, we compared their repertoire with that of publicly available 262 immunoglobulin heavy variable domain gene rearrangement sequences from systemic ABC-type DLBCLs. PVRL displayed a strikingly biased repertoire, with the IGHV4-34 gene being used in 63.6% of cases, which was significantly higher than in PCNSL (34.7%) or in DLBCL (30.2%). Further repertoire bias was evident by (1) restricted associations of IGHV4-34 expressing heavy chains, with κ light chains utilizing the IGKV3-20/IGKJ1 gene pair, including 5 cases with quasi-identical sequences, and (2) the presence of a subset of stereotyped IGHV3-7 rearrangements. All PVRL IGHV sequences were highly mutated, with evidence of antigen selection and ongoing mutations. Finally, half of PVRL and PCNSL cases carried the MYD88 L265P mutation, which was present in all 4 PVRL cases with stereotyped IGHV3-7 rearrangements. In conclusion, the massive bias in the immunoglobulin gene repertoire of PVRL delineates it from PCNSL and points to antigen selection as a major driving force in their development.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2019000980

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 2876449-3

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1574-1574

Abstract: Abstract 1574 Primary intraocular lymphoma (PIOL) is a high grade lymphoma, which affects the retina, vitreous and/or the optic nerve. The vast majority of cases are classified as diffuse large B cell lymphoma and considered as a subtype of primary central nervous system lymphoma (PCNSL). Because of its rarity, only very few studies have been performed on immunoglobulin (IG) gene repertoire of PIOL mostly in very small series. We here report results from the detailed immunogenetic analysis of the clonal IGHV-IGHD-IGHJ rearrangements in 30 cases of PIOL, the largest series to date. We observed a highly restricted IGHV usage, with a single gene, namely IGHV4-34, present in two thirds of cases (20/30). The second most frequent gene was IGHV3-7, utilized in 10% (3/30) of cases. Thus, only two IGHV genes accounted for more than three quarters of the PIOL repertoire. IGHD3 and IGHD2 subgroup genes were by far the two most frequently used, respectively in 51.9% (14/30) and 27.9% (7/30) of cases. In contrast, the IGHD6 subgroup genes, commonly used in other B cell malignancies, were not detected in any PIOL IGH rearrangement. While IGHJ4 was found in 40% (12/30) cases, IGHJ usage was unusual for the IGHJ5 and IGHJ6 genes, as the former clearly predominated over the latter (10/30 cases, 33.3% vs 4/30 cases, 13.3%). Heavy complementarity-determining region 3 (VH CDR3) length ranged from 7 up to 27 amino acids (median, 14). Twenty of 30 cases carried electropositive VH CDR3s with predicted isoelectric values of 7.0 or greater (up to 13.0). Remarkably, all 3 cases expressing the IGHV3-7 gene had 11 aminoacid-long, electropositive VH CDR3s with shared motifs, enabling their assignment to a cluster with “stereotyped” antigen-binding sites. Except for two unmutated cases, all sequences had a high number of somatic mutations as the mean % of identity from their germline counterpart was 85.9% (range 77.7% to 95.5%). Analysis of the distribution of somatic hypermutation (SHM) in the subgroup of PIOL cases utilizing the IGHV4-34 gene revealed high replacement (R) to silent (S) mutation ratios in CDRs (R/S 〉 3.0) along with low R/S ratios in FRs. Shared replacement mutations (“stereotyped” amino acid (AA) changes) at certain codon positions were identified amongst rearrangements utilizing the IGHV4-34 gene, alluding to an antigen-driven SHM process. Several AA changes identified here were distinct from those previously reported for IGHV4-34 rearrangements in other B cell malignancies, in particular chronic lymphocytic leukemia, mantle-cell lymphoma or Burkitt's lymphoma, and thus can be considered as “PIOL-biased”. In addition, the IGVH4-34 specific motif responsible for binding in superantigenic fashion the N-acetyllactosamine antigenic determinant was altered in only 2/20 IGVH4-34 PIOL sequences; however, the most critical residue of this motif (TRP at position 7 in FR1) was intact in all 20 cases. On these grounds, it could be hypothesized that despite intense SHM activity, these clones retained the ability to bind to and be activated by superantigens. Sequencing multiple clones (13 to 17) in three cases demonstrated intraclonal diversity in all of them, indicating ongoing mutational activity. In conclusion PIOL displays a highly biased IG gene repertoire with very precise targeting and distinctive features of SHM, suggestive of selection by specific (super)antigen(s) in lymphomagenesis. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.1574.1574

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1479-1479

Abstract: B cells residing the marginal zone (MZ) provide a first line of defense against blood borne pathogens, producing the greater part of circulating natural antibodies conferring protection against infection. Dysregulated homeostasis and function of MZ B cells has been implicated in a wide range of B lymphoproliferations, encompassing the distinct MZ lymphomas recognized by the WHO Classification, the related provisional entities and even chronic lymphocytic leukemia (CLL), for which a MZ derivation has been proposed. Here, taking advantage of a large multi-institutional series, we aimed at obtaining insight into the ontogenetic relationship of MZ lymphoproliferations, related entities and CLL through cross-comparison of their B cell receptor immunoglobulin (BcR IG) gene repertoires. Our sequence dataset included 3660 unique IGHV-IGHD-IGHJ gene rearrangement sequences from our collaborative centers and/or public databases derived from: (1) MZ lymphomas: splenic (SMZL), n=379; nodal (NMZL), n=37; extranodal (ENMZL), n=95; (2) provisional entities of postulated MZ origin, including splenic diffuse red pulp lymphoma (SDRL, n=16) and clonal B cell lymphocytosis of MZ origin (CBL-MZ, n=60); (3) persistent polyclonal B cell lymphocytosis (PPBL), n=286 (from 2 cases); (4) MZ cells isolated from six spleen specimens free of neoplastic cells at histological inspection (non-malignant MZ), obtained at surgery for cancer, n=489; (5) autoimmune conditions, n=1243; (6) various types of normal B cells, n=1055. The most pronounced IG gene repertoire skewing was observed in SMZL with the IGHV1-2*04 gene accounting for 26% of cases. Restrictions, though less striking, were also identified in the other MZ lymphomas as well: (i) the IGHV4-34 gene predominated in NMZL (14.3%); and, (ii) the IGHV1-69 gene predominated in ENMZL (14.6%), albeit with significantly different distribution depending on the primary site of involvement, ranging from 38% in salivary ENMZL to 11% in gastric ENMZL to 4% in ocular adnexa ENMZL (p 〈 0.01). The vast majority of MZL cases showed at least some impact of somatic hypermutation (SHM), with the proportion of cases lacking any SHM ranging from 0% in salivary ENMZ to only 13% in SMZL. Following established bioinformatics approaches, we searched for stereotyped BcR IG sequences i.e. IGHV-IGHD-IGHJ gene rearrangements with restricted antigen-binding site sequence motifs. For the purposes of this analysis, the present sequence dataset was cross-compared to a large dataset of 20451 IGHV-IGHD-IGHJ gene rearrangement sequences from CLL patients from the IMGT/CLL-DB. Overall, 6437 different clusters with stereotyped BcR IG sequences were identified in the merged dataset, including from only 2 to more than 350 sequences. Two categories of clusters with stereotyped BcR IG were identified: disease-specific (n=4813) and 'mixed' (n=1624) i.e. comprised of cases with different diagnosis. The great majority of clusters in the former category concerned exclusively CLL and corresponded to well-established CLL stereotyped subsets, while only a small minority concerned exclusively MZ lymphomas, all with a diagnosis of SMZL. Mixed clusters were relatively small in size, with only 4 populated by more than 10 cases; of these, 2 utilized the IGHV1-69 gene, while the remaining 2 utilized the IGHV3-7 and IGHV4-59 gene, respectively. They comprised rearrangements from various entities, including SMZL, ENMZL (gastric, salivary gland, ocular adnexa), CLL, hepatitis C virus-associated diffuse large B cell lymphoma (DLBCL), but also rheumatoid factors and non-malignant spleen MZ cells. Notably, shared (recurrent) amino acid changes introduced by SHM (i.e. the same amino acid replacement at the same position) were identified in each mixed cluster. In conclusion, we document different immunogenetic signatures for MZ lymphomas, with limited overlap both amongst the various distinct and provisional WHO entities but also versus CLL. These findings indicate distinct antigen exposure histories and/or different (micro)environments underlying the ontogeny of MZ lymphomas. That said, the existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms, may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Disclosures Ghia: Janssen Pharmaceuticals: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1479.1479

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: The Journal of Pathology, Wiley, Vol. 247, No. 4 ( 2019-04), p. 416-421

Abstract: The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas ( n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities ( n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross‐entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ‐related or not; n = 65 837) revealed four major clusters of cases sharing homologous (‘public’) heavy variable complementarity‐determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non‐malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen‐triggered, immune‐mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Type of Medium: Online Resource

ISSN: 0022-3417 , 1096-9896

URL: Issue

URL: Article

DOI: 10.1002/path.2019.247.issue-4

DOI: 10.1002/path.5209

Language: English

Publisher: Wiley

Publication Date: 2019

detail.hit.zdb_id: 1475280-3