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DOI 10.1182/blood-2022-169429
Autonomous BCR Signaling and Genetic Aberrations in CLL-Phenotype Monoclonal B Lymphocytosis in Siblings of CLL Patients
2022-11-15
Sepulveda Yañez, Julieta Haydee
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Quinten, Edwin
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Koning, Marvyn T.
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Eken, Janneke A.
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Pfeifer, Dietmar
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De Groen, Ruben A. L.
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Alvarez Saravia, Diego
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Agathangelidis, Andreas
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van Bergen, Cornelis A. M.
;
Stamatopoulos, Kostas
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DOI 10.1182/blood-2022-169429
Autonomous BCR Signaling and Genetic Aberrations in CLL-Phenotype Monoclonal B Lymphocytosis in Siblings of CLL Patients
2022-11-15
Sepulveda Yañez, Julieta Haydee
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Quinten, Edwin
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Koning, Marvyn T.
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Eken, Janneke A.
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Pfeifer, Dietmar
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De Groen, Ruben A. L.
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Alvarez Saravia, Diego
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Agathangelidis, Andreas
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van Bergen, Cornelis A. M.
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Stamatopoulos, Kostas
7
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DOI 10.3389/fimmu.2021.807015
Tandem Substitutions in Somatic Hypermutation
2022-01-07
Sepulveda Yañez, Julieta Haydee
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Alvarez Saravia, Diego
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Pilzecker, Bas
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van Schouwenburg, Pauline A.
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van den Burg, Mirjam
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Veelken, Hendrik
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Navarrete Signorile, Marcelo Alejandro
;
Jacobs, Heinz
;
Koning, Marvyn T.
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.
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DOI 10.3389/fimmu.2021.807015
Tandem Substitutions in Somatic Hypermutation
2022-01-07
Sepulveda Yañez, Julieta Haydee
;
Alvarez Saravia, Diego
;
Pilzecker, Bas
;
van Schouwenburg, Pauline A.
;
van den Burg, Mirjam
;
Veelken, Hendrik
;
Navarrete Signorile, Marcelo Alejandro
;
Jacobs, Heinz
;
Koning, Marvyn T.
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.
Scopus© Citations 3
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DOI 10.3390/ijms222313015
Integration of Mutational Signature Analysis with 3D Chromatin Data Unveils Differential AID-Related Mutagenesis in Indolent Lymphomas
2021-12
Sepulveda Yañez, Julieta Haydee
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Alvarez-Saravia, Diego
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Fernández Goycoolea, José Antonio
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Aldridge, Jacqueline
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van Bergen, Cornelis A. M.
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Posthuma, Ward
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Uribe Paredes, Roberto Alex
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Veelken, Hendrik
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Navarrete Signorile, Marcelo Alejandro
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 (p = 0.02) in FL than CLL. These data indicate that AID activity drives the genetic landscapes of FL and CLL. However, the final result of AID-induced mutagenesis differs between these lymphomas depending on chromatin compartmentalization and mutations in DNA repair pathways.
Scopus© Citations 2 4
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DOI 10.1182/blood-2021-150475
"Snapshotting" Somatic Hypermutation in Single Follicular Lymphoma Cells
2021-11-23
Sepulveda Yañez, Julieta Haydee
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Alvarez-Saravia, Diego
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Quinten, Edwin
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Menafra, Roberta
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Kloet, Susan L.
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Monajemi, Ramin
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Kielbasa, Szymon M.
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Navarrete Signorile, Marcelo Alejandro
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van Bergen, Cornelis A. M.
;
Veelken, Hendrik
1
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DOI 10.1182/blood-2019-130508
High-Throughput BCR Sequencing and Single-Cell Transcriptomics Reveal Distinct Transcriptional Profiles Associated with Subclonal Evolution of Follicular Lymphoma
2019-11-13
van Bergen, Cornelis A. M.
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Koning, Marvyn T.
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Quinten, Edwin
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Mykowiecka, Agnieszka
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Sepulveda Yañez, Julieta Haydee
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Monajemi, Ramin
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De Groen, Ruben A. L.
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Vermaat, Joost
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Kloet, Susan L.
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Kielbasa, Szymon M.
1
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DOI 10.1182/blood-2018-99-116174
Differential Genome-Wide Mutational Patterns in Indolent B-Cell Lymphomas
2018-11-29
Sepulveda Yañez, Julieta Haydee
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Alvarez, Diego
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Fernández Goycoolea, José Antonio
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van Bergen, Cornelis A. M.
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Veelken, Hendrik
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Navarrete Signorile, Marcelo Alejandro
1
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DOI 10.3389/fimmu.2019.01543
Peripheral IgE Repertoires of Healthy Donors Carry Moderate Mutation Loads and Do Not Overlap With Other Isotypes
2019-7-3
Koning, Marvyn T.
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Trollmann, Ignis J. M.
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van Bergen, Cornelis A. M.
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Saravia, Diego Alvarez
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Navarrete Signorile, Marcelo Alejandro
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Kielbasa, Szymon M.
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Veelken, Hendrik
IgE-mediated allergic disease represents an increasing health problem. Although numerous studies have investigated IgE sequences in allergic patients, little information is available on the healthy IgE repertoire. IgM, IgG, IgA, and IgE transcripts from peripheral blood B cells of five healthy, non-atopic individuals were amplified by unbiased, template-switching, isotype-specific PCR. Complete VDJ regions were sequenced to near-exhaustion on the PacBio platform. Sequences were analyzed for clonal relationships, degree of somatic hypermutation, IGHV gene usage, evidence of antigenic selection, and N-linked glycosylation motifs. IgE repertoires appeared to be highly oligoclonal with preferential usage of certain IGHV genes compared to the other isotypes. IgE sequences carried more somatic mutations than IgM, yet fewer than IgG and IgA. Many IgE sequences contained N-linked glycosylation motifs. IgE sequences had no clonal relationship with the other isotypes. The IgE repertoire in healthy individuals is derived from relatively few clonal expansions without apparent relations to immune reactions that give rise to IgG or IgA. The mutational burden of normal IgE suggests an origin through direct class-switching from the IgM repertoire with little evidence of antigenic drive, and hence presumably low affinity for specific antigens. These findings are compatible with a primary function of the healthy IgE repertoire to occupy Fc epsilon receptors for competitive protection against mast cell degranulation induced by allergen-specific, high-affinity IgE. This background knowledge may help to elucidate pathogenic mechanisms in allergic disease and to design improved desensitization strategies.
Scopus© Citations 14 1

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