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Evidence of somatic hypermutation in the antigen binding sites of patients with CLL harboring IGHV genes with 100% germline identity

Classification of patients with chronic lymphocytic leukemia (CLL) based on the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene has established predictive and prognostic relevance. The SHM status is assessed based on the number of mutations within the I...

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Autores principales: Sofou, Electra, Zaragoza-Infante, Laura, Pechlivanis, Nikolaos, Karakatsoulis, Georgios, Notopoulou, Sofia, Stavroyianni, Niki, Psomopoulos, Fotis, Georgiou, Elisavet, de Septenville, Anne Langlois, Davi, Frederic, Agathangelidis, Andreas, Chatzidimitriou, Anastasia, Stamatopoulos, Kostas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9795043/
https://www.ncbi.nlm.nih.gov/pubmed/36591518
http://dx.doi.org/10.3389/fonc.2022.1079772
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author Sofou, Electra
Zaragoza-Infante, Laura
Pechlivanis, Nikolaos
Karakatsoulis, Georgios
Notopoulou, Sofia
Stavroyianni, Niki
Psomopoulos, Fotis
Georgiou, Elisavet
de Septenville, Anne Langlois
Davi, Frederic
Agathangelidis, Andreas
Chatzidimitriou, Anastasia
Stamatopoulos, Kostas
author_facet Sofou, Electra
Zaragoza-Infante, Laura
Pechlivanis, Nikolaos
Karakatsoulis, Georgios
Notopoulou, Sofia
Stavroyianni, Niki
Psomopoulos, Fotis
Georgiou, Elisavet
de Septenville, Anne Langlois
Davi, Frederic
Agathangelidis, Andreas
Chatzidimitriou, Anastasia
Stamatopoulos, Kostas
author_sort Sofou, Electra
collection PubMed
description Classification of patients with chronic lymphocytic leukemia (CLL) based on the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene has established predictive and prognostic relevance. The SHM status is assessed based on the number of mutations within the IG heavy variable domain sequence, albeit only over the rearranged IGHV gene excluding the variable heavy complementarity determining region 3 (VH CDR3). This may lead to an underestimation of the actual impact of SHM, in fact overlooking the most critical region for antigen-antibody interactions, i.e. the VH CDR3. Here we investigated whether SHM may be present within the VH CDR3 of cases bearing ‘truly unmutated’ IGHV genes (i.e. 100% germline identity across VH FR1-VH FR3) employing Next Generation Sequencing. We studied 16 patients bearing a ‘truly unmutated’ CLL clone assigned to stereotyped subsets #1 (n=12) and #6 (n=4). We report the existence of SHM within the germline-encoded 3’IGHV, IGHD, 5’IGHJ regions of the VH CDR3 in both the main IGHV-IGHD-IGHJ gene clonotype and its variants. Recurrent somatic mutations were identified between different patients of the same subset, supporting the notion that they represent true mutational events rather than technical artefacts; moreover, they were located adjacent to/within AID hotspots, pointing to SHM as the underlying mechanism. In conclusion, we provide immunogenetic evidence for intra-VH CDR3 variations, attributed to SHM, in CLL patients carrying ‘truly unmutated’ IGHV genes. Although the clinical implications of this observation remain to be defined, our findings offer a new perspective into the immunobiology of CLL, alluding to the operation of VH CDR3-restricted SHM in U-CLL.
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spelling pubmed-97950432022-12-29 Evidence of somatic hypermutation in the antigen binding sites of patients with CLL harboring IGHV genes with 100% germline identity Sofou, Electra Zaragoza-Infante, Laura Pechlivanis, Nikolaos Karakatsoulis, Georgios Notopoulou, Sofia Stavroyianni, Niki Psomopoulos, Fotis Georgiou, Elisavet de Septenville, Anne Langlois Davi, Frederic Agathangelidis, Andreas Chatzidimitriou, Anastasia Stamatopoulos, Kostas Front Oncol Oncology Classification of patients with chronic lymphocytic leukemia (CLL) based on the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene has established predictive and prognostic relevance. The SHM status is assessed based on the number of mutations within the IG heavy variable domain sequence, albeit only over the rearranged IGHV gene excluding the variable heavy complementarity determining region 3 (VH CDR3). This may lead to an underestimation of the actual impact of SHM, in fact overlooking the most critical region for antigen-antibody interactions, i.e. the VH CDR3. Here we investigated whether SHM may be present within the VH CDR3 of cases bearing ‘truly unmutated’ IGHV genes (i.e. 100% germline identity across VH FR1-VH FR3) employing Next Generation Sequencing. We studied 16 patients bearing a ‘truly unmutated’ CLL clone assigned to stereotyped subsets #1 (n=12) and #6 (n=4). We report the existence of SHM within the germline-encoded 3’IGHV, IGHD, 5’IGHJ regions of the VH CDR3 in both the main IGHV-IGHD-IGHJ gene clonotype and its variants. Recurrent somatic mutations were identified between different patients of the same subset, supporting the notion that they represent true mutational events rather than technical artefacts; moreover, they were located adjacent to/within AID hotspots, pointing to SHM as the underlying mechanism. In conclusion, we provide immunogenetic evidence for intra-VH CDR3 variations, attributed to SHM, in CLL patients carrying ‘truly unmutated’ IGHV genes. Although the clinical implications of this observation remain to be defined, our findings offer a new perspective into the immunobiology of CLL, alluding to the operation of VH CDR3-restricted SHM in U-CLL. Frontiers Media S.A. 2022-12-14 /pmc/articles/PMC9795043/ /pubmed/36591518 http://dx.doi.org/10.3389/fonc.2022.1079772 Text en Copyright © 2022 Sofou, Zaragoza-Infante, Pechlivanis, Karakatsoulis, Notopoulou, Stavroyianni, Psomopoulos, Georgiou, de Septenville, Davi, Agathangelidis, Chatzidimitriou and Stamatopoulos https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Sofou, Electra
Zaragoza-Infante, Laura
Pechlivanis, Nikolaos
Karakatsoulis, Georgios
Notopoulou, Sofia
Stavroyianni, Niki
Psomopoulos, Fotis
Georgiou, Elisavet
de Septenville, Anne Langlois
Davi, Frederic
Agathangelidis, Andreas
Chatzidimitriou, Anastasia
Stamatopoulos, Kostas
Evidence of somatic hypermutation in the antigen binding sites of patients with CLL harboring IGHV genes with 100% germline identity
title Evidence of somatic hypermutation in the antigen binding sites of patients with CLL harboring IGHV genes with 100% germline identity
title_full Evidence of somatic hypermutation in the antigen binding sites of patients with CLL harboring IGHV genes with 100% germline identity
title_fullStr Evidence of somatic hypermutation in the antigen binding sites of patients with CLL harboring IGHV genes with 100% germline identity
title_full_unstemmed Evidence of somatic hypermutation in the antigen binding sites of patients with CLL harboring IGHV genes with 100% germline identity
title_short Evidence of somatic hypermutation in the antigen binding sites of patients with CLL harboring IGHV genes with 100% germline identity
title_sort evidence of somatic hypermutation in the antigen binding sites of patients with cll harboring ighv genes with 100% germline identity
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9795043/
https://www.ncbi.nlm.nih.gov/pubmed/36591518
http://dx.doi.org/10.3389/fonc.2022.1079772
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