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  1. Article ; Online: Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL.

    Eken, Janneke A / Koning, Marvyn T / Kupcova, Kristyna / Sepúlveda Yáñez, Julieta H / de Groen, Ruben A L / Quinten, Edwin / Janssen, Jurriaan / van Bergen, Cornelis A M / Vermaat, Joost S P / Cleven, Arjen / Navarrete, Marcelo A / Ylstra, Bauke / de Jong, Daphne / Havranek, Ondrej / Jumaa, Hassan / Veelken, Hendrik

    The Journal of experimental medicine

    2024  Volume 221, Issue 5

    Abstract: Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR ... ...

    Abstract Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR signaling cascade in a minority of cases. We demonstrate that autonomous BCR signaling, akin to its essential pathogenetic role in chronic lymphocytic leukemia (CLL), can explain chronic active BCR signaling in ABC-DLBCL. 13 of 18 tested DLBCL-derived BCR, including 12 cases selected for expression of IgM, induced spontaneous calcium flux and increased phosphorylation of the BCR signaling cascade in murine triple knockout pre-B cells without antigenic stimulation or external BCR crosslinking. Autonomous BCR signaling was associated with IgM isotype, dependent on somatic BCR mutations and individual HCDR3 sequences, and largely restricted to non-GCB DLBCL. Autonomous BCR signaling represents a novel immunological oncogenic driver mechanism in DLBCL originating from individual BCR sequences and adds a new dimension to currently proposed genetics- and transcriptomics-based DLBCL classifications.
    MeSH term(s) Animals ; Mice ; B-Lymphocytes ; Lymphoma, Large B-Cell, Diffuse/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell ; Receptors, Antigen, B-Cell ; Immunoglobulin M
    Chemical Substances Receptors, Antigen, B-Cell ; Immunoglobulin M
    Language English
    Publishing date 2024-03-21
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20230941
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ua VI Zs.107: Show issues Location:
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    Zs.MG 45: Show issues

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  2. Article ; Online: Acquisition of a glycosylated B-cell receptor drives follicular lymphoma toward a dark zone phenotype.

    van Bergen, Cornelis A M / Kloet, Susan L / Quinten, Edwin / Sepúlveda Yáñez, Julieta H / Menafra, Roberta / Griffioen, Marieke / Jansen, Patty M / Koning, Marvyn T / Knijnenburg, Jeroen / Navarrete, Marcelo A / Kiełbasa, Szymon M / Veelken, Hendrik

    Blood advances

    2023  Volume 7, Issue 19, Page(s) 5812–5816

    Language English
    Publishing date 2023-07-24
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2915908-8
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2023010725
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 7153: Show issues Location:
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  3. Article ; Online: Autonomous B-cell receptor signaling and genetic aberrations in chronic lymphocytic leukemia-phenotype monoclonal B lymphocytosis in siblings of patients with chronic lymphocytic leukemia.

    Quinten, Edwin / Sepúlveda-Yáñez, Julieta H / Koning, Marvyn T / Eken, Janneke A / Pfeifer, Dietmar / Nteleah, Valeri / De Groen, Ruben A L / Saravia, Diego Alvarez / Knijnenburg, Jeroen / Stuivenberg-Bleijswijk, Hedwig E / Pantic, Milena / Agathangelidis, Andreas / Keppler-Hafkemeyer, Andrea / Van Bergen, Cornelis A M / Uribe-Paredes, Roberto / Stamatopoulos, Kostas / Vermaat, Joost S P / Zirlik, Katja / Navarrete, Marcelo A /
    Jumaa, Hassan / Veelken, Hendrik

    Haematologica

    2024  Volume 109, Issue 3, Page(s) 824–834

    Abstract: Clonal expansion of CD5-expressing B cells, commonly designated as monoclonal B lymphocytosis (MBL), is a precursor condition for chronic lymphocytic leukemia (CLL). The mechanisms driving subclinical MBL B-cell expansion and progression to CLL, ... ...

    Abstract Clonal expansion of CD5-expressing B cells, commonly designated as monoclonal B lymphocytosis (MBL), is a precursor condition for chronic lymphocytic leukemia (CLL). The mechanisms driving subclinical MBL B-cell expansion and progression to CLL, occurring in approximately 1% of affected individuals, are unknown. An autonomously signaling B-cell receptor (BCR) is essential for the pathogenesis of CLL. The objectives of this study were functional characterization of the BCR of MBL in siblings of CLL patients and a comparison of genetic variants in MBL-CLL sibling pairs. Screening of peripheral blood by flow cytometry detected 0.2-480 clonal CLL-phenotype cells per microliter (median: 37/μL) in 34 of 191 (17.8%) siblings of CLL patients. Clonal BCR isolated from highly purified CLL-phenotype cells induced robust calcium mobilization in BCR-deficient murine pre-B cells in the absence of external antigen and without experimental crosslinking. This autonomous BCR signal was less intense than the signal originating from the CLL BCR of their CLL siblings. According to genotyping by single nucleotide polymorphism array, whole exome, and targeted panel sequencing, CLL risk alleles were found with high and similar prevalence in CLL patients and MBL siblings, respectively. Likewise, the prevalence of recurrent CLL-associated genetic variants was similar between CLL and matched MBL samples. However, copy number variations and small variants were frequently subclonal in MBL cells, suggesting their acquisition during subclinical clonal expansion. These findings support a stepwise model of CLL pathogenesis, in which autonomous BCR signaling leads to a non-malignant (oligo)clonal expansion of CD5+ B cells, followed by malignant progression to CLL after acquisition of pathogenic genetic variants.
    MeSH term(s) Humans ; Animals ; Mice ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Siblings ; DNA Copy Number Variations ; Lymphocytosis/genetics ; Leukemia ; Receptors, Antigen, B-Cell/genetics ; Phenotype
    Chemical Substances Receptors, Antigen, B-Cell
    Language English
    Publishing date 2024-03-01
    Publishing country Italy
    Document type Journal Article
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2022.282542
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.76: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Tandem Substitutions in Somatic Hypermutation.

    Sepúlveda-Yáñez, Julieta H / Alvarez Saravia, Diego / Pilzecker, Bas / van Schouwenburg, Pauline A / van den Burg, Mirjam / Veelken, Hendrik / Navarrete, Marcelo A / Jacobs, Heinz / Koning, Marvyn T

    Frontiers in immunology

    2022  Volume 12, Page(s) 807015

    Abstract: Upon antigen recognition, activation-induced cytosine deaminase initiates affinity maturation of the B-cell receptor by somatic hypermutation (SHM) through error-prone DNA repair pathways. SHM typically creates single nucleotide substitutions, but tandem ...

    Abstract Upon antigen recognition, activation-induced cytosine deaminase initiates affinity maturation of the B-cell receptor by somatic hypermutation (SHM) through error-prone DNA repair pathways. SHM typically creates single nucleotide substitutions, but tandem substitutions may also occur. We investigated incidence and sequence context of tandem substitutions by massive parallel sequencing of V(D)J repertoires in healthy human donors. Mutation patterns were congruent with SHM-derived single nucleotide mutations, delineating initiation of the tandem substitution by AID. Tandem substitutions comprised 5,7% of AID-induced mutations. The majority of tandem substitutions represents single nucleotide juxtalocations of directly adjacent sequences. These observations were confirmed in an independent cohort of healthy donors. We propose a model where tandem substitutions are predominantly generated by translesion synthesis across an apyramidinic site that is typically created by UNG. During replication, apyrimidinic sites transiently adapt an extruded configuration, causing skipping of the extruded base. Consequent strand decontraction leads to the juxtalocation, after which exonucleases repair the apyramidinic site and any directly adjacent mismatched base pairs. The mismatch repair pathway appears to account for the remainder of tandem substitutions. Tandem substitutions may enhance affinity maturation and expedite the adaptive immune response by overcoming amino acid codon degeneracies or mutating two adjacent amino acid residues simultaneously.
    MeSH term(s) Alleles ; Codon ; DNA Mismatch Repair ; High-Throughput Nucleotide Sequencing ; Humans ; Immunoglobulin Heavy Chains/genetics ; Mutation ; Receptors, Antigen, B-Cell/genetics ; Somatic Hypermutation, Immunoglobulin ; Tandem Repeat Sequences ; V(D)J Recombination
    Chemical Substances Codon ; Immunoglobulin Heavy Chains ; Receptors, Antigen, B-Cell
    Language English
    Publishing date 2022-01-07
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2021.807015
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Integration of Mutational Signature Analysis with 3D Chromatin Data Unveils Differential AID-Related Mutagenesis in Indolent Lymphomas.

    Sepulveda-Yanez, Julieta H / Alvarez-Saravia, Diego / Fernandez-Goycoolea, Jose / Aldridge, Jacqueline / van Bergen, Cornelis A M / Posthuma, Ward / Uribe-Paredes, Roberto / Veelken, Hendrik / Navarrete, Marcelo A

    International journal of molecular sciences

    2021  Volume 22, Issue 23

    Abstract: Activation-induced deaminase (AID) is required for somatic hypermutation in immunoglobulin genes, but also induces off-target mutations. Follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL), the most frequent types of indolent B-cell tumors, ... ...

    Abstract Activation-induced deaminase (AID) is required for somatic hypermutation in immunoglobulin genes, but also induces off-target mutations. Follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL), the most frequent types of indolent B-cell tumors, are exposed to AID activity during lymphomagenesis. We designed a workflow integrating de novo mutational signatures extraction and fitting of COSMIC (Catalogue Of Somatic Mutations In Cancer) signatures, with tridimensional chromatin conformation data (Hi-C). We applied the workflow to exome sequencing data from lymphoma samples. In 33 FL and 30 CLL samples, 42% and 34% of the contextual mutations could be traced to a known AID motif. We demonstrate that both CLL and FL share mutational processes dominated by spontaneous deamination, failures in DNA repair, and AID activity. The processes had equiproportional distribution across active and nonactive chromatin compartments in CLL. In contrast, canonical AID activity and failures in DNA repair pathways in FL were significantly higher within the active chromatin compartment. Analysis of DNA repair genes revealed a higher prevalence of base excision repair gene mutations (
    MeSH term(s) Alleles ; Chromatin/metabolism ; Cytidine Deaminase/genetics ; DNA Mutational Analysis ; DNA Repair/genetics ; Databases, Genetic ; Gene Frequency ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Lymphoma, Follicular/genetics ; Lymphoma, Follicular/pathology ; Polymorphism, Single Nucleotide
    Chemical Substances Chromatin ; AICDA (activation-induced cytidine deaminase) (EC 3.5.4.-) ; Cytidine Deaminase (EC 3.5.4.5)
    Language English
    Publishing date 2021-12-01
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms222313015
    Database MEDical Literature Analysis and Retrieval System OnLINE

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