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Post-Transformation IGHV-IGHD-IGHJ Mutations in Chronic Lymphocytic Leukemia B Cells: Implications for Mutational Mechanisms and Impact on Clinical Course

Analyses of IGHV gene mutations in chronic lymphocytic leukemia (CLL) have had a major impact on the prognostication and treatment of this disease. A hallmark of IGHV-mutation status is that it very rarely changes clonally over time. Nevertheless, targeted and deep DNA sequencing of IGHV-IGHD-IGHJ r...

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Autores principales: Bagnara, Davide, Tang, Catherine, Brown, Jennifer R., Kasar, Siddha, Fernandes, Stacey, Colombo, Monica, Vergani, Stefano, Mazzarello, Andrea N., Ghiotto, Fabio, Bruno, Silvia, Morabito, Fortunato, Rai, Kanti R., Kolitz, Jonathan E., Barrientos, Jacqueline C., Allen, Steven L., Fais, Franco, Scharff, Matthew D., MacCarthy, Thomas, Chiorazzi, Nicholas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186829/
https://www.ncbi.nlm.nih.gov/pubmed/34113563
http://dx.doi.org/10.3389/fonc.2021.640731
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author Bagnara, Davide
Tang, Catherine
Brown, Jennifer R.
Kasar, Siddha
Fernandes, Stacey
Colombo, Monica
Vergani, Stefano
Mazzarello, Andrea N.
Ghiotto, Fabio
Bruno, Silvia
Morabito, Fortunato
Rai, Kanti R.
Kolitz, Jonathan E.
Barrientos, Jacqueline C.
Allen, Steven L.
Fais, Franco
Scharff, Matthew D.
MacCarthy, Thomas
Chiorazzi, Nicholas
author_facet Bagnara, Davide
Tang, Catherine
Brown, Jennifer R.
Kasar, Siddha
Fernandes, Stacey
Colombo, Monica
Vergani, Stefano
Mazzarello, Andrea N.
Ghiotto, Fabio
Bruno, Silvia
Morabito, Fortunato
Rai, Kanti R.
Kolitz, Jonathan E.
Barrientos, Jacqueline C.
Allen, Steven L.
Fais, Franco
Scharff, Matthew D.
MacCarthy, Thomas
Chiorazzi, Nicholas
author_sort Bagnara, Davide
collection PubMed
description Analyses of IGHV gene mutations in chronic lymphocytic leukemia (CLL) have had a major impact on the prognostication and treatment of this disease. A hallmark of IGHV-mutation status is that it very rarely changes clonally over time. Nevertheless, targeted and deep DNA sequencing of IGHV-IGHD-IGHJ regions has revealed intraclonal heterogeneity. We used a DNA sequencing approach that achieves considerable depth and minimizes artefacts and amplification bias to identify IGHV-IGHD-IGHJ subclones in patients with prolonged temporal follow-up. Our findings extend previous studies, revealing intraclonal IGHV-IGHD-IGHJ diversification in almost all CLL clones. Also, they indicate that some subclones with additional IGHV-IGHD-IGHJ mutations can become a large fraction of the leukemic burden, reaching numerical criteria for monoclonal B-cell lymphocytosis. Notably, the occurrence and complexity of post-transformation IGHV-IGHD-IGHJ heterogeneity and the expansion of diversified subclones are similar among U-CLL and M-CLL patients. The molecular characteristics of the mutations present in the parental, clinically dominant CLL clone (CDC) differed from those developing post-transformation (post-CDC). Post-CDC mutations exhibit significantly lower fractions of mutations bearing signatures of activation induced deaminase (AID) and of error-prone repair by Polη, and most of the mutations were not ascribable to those enzymes. Additionally, post-CDC mutations displayed a lower percentage of nucleotide transitions compared with transversions that was also not like the action of AID. Finally, the post-CDC mutations led to significantly lower ratios of replacement to silent mutations in VH CDRs and higher ratios in VH FRs, distributions different from mutations found in normal B-cell subsets undergoing an AID-mediated process. Based on these findings, we propose that post-transformation mutations in CLL cells either reflect a dysfunctional standard somatic mutational process or point to the action of another mutational process not previously associated with IG V gene loci. If the former option is the case, post-CDC mutations could lead to a lesser dependence on antigen dependent BCR signaling and potentially a greater influence of off-target, non-IG genomic mutations. Alternatively, the latter activity could add a new stimulatory survival/growth advantage mediated by the BCR through structurally altered FRs, such as that occurring by superantigen binding and stimulation.
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spelling pubmed-81868292021-06-09 Post-Transformation IGHV-IGHD-IGHJ Mutations in Chronic Lymphocytic Leukemia B Cells: Implications for Mutational Mechanisms and Impact on Clinical Course Bagnara, Davide Tang, Catherine Brown, Jennifer R. Kasar, Siddha Fernandes, Stacey Colombo, Monica Vergani, Stefano Mazzarello, Andrea N. Ghiotto, Fabio Bruno, Silvia Morabito, Fortunato Rai, Kanti R. Kolitz, Jonathan E. Barrientos, Jacqueline C. Allen, Steven L. Fais, Franco Scharff, Matthew D. MacCarthy, Thomas Chiorazzi, Nicholas Front Oncol Oncology Analyses of IGHV gene mutations in chronic lymphocytic leukemia (CLL) have had a major impact on the prognostication and treatment of this disease. A hallmark of IGHV-mutation status is that it very rarely changes clonally over time. Nevertheless, targeted and deep DNA sequencing of IGHV-IGHD-IGHJ regions has revealed intraclonal heterogeneity. We used a DNA sequencing approach that achieves considerable depth and minimizes artefacts and amplification bias to identify IGHV-IGHD-IGHJ subclones in patients with prolonged temporal follow-up. Our findings extend previous studies, revealing intraclonal IGHV-IGHD-IGHJ diversification in almost all CLL clones. Also, they indicate that some subclones with additional IGHV-IGHD-IGHJ mutations can become a large fraction of the leukemic burden, reaching numerical criteria for monoclonal B-cell lymphocytosis. Notably, the occurrence and complexity of post-transformation IGHV-IGHD-IGHJ heterogeneity and the expansion of diversified subclones are similar among U-CLL and M-CLL patients. The molecular characteristics of the mutations present in the parental, clinically dominant CLL clone (CDC) differed from those developing post-transformation (post-CDC). Post-CDC mutations exhibit significantly lower fractions of mutations bearing signatures of activation induced deaminase (AID) and of error-prone repair by Polη, and most of the mutations were not ascribable to those enzymes. Additionally, post-CDC mutations displayed a lower percentage of nucleotide transitions compared with transversions that was also not like the action of AID. Finally, the post-CDC mutations led to significantly lower ratios of replacement to silent mutations in VH CDRs and higher ratios in VH FRs, distributions different from mutations found in normal B-cell subsets undergoing an AID-mediated process. Based on these findings, we propose that post-transformation mutations in CLL cells either reflect a dysfunctional standard somatic mutational process or point to the action of another mutational process not previously associated with IG V gene loci. If the former option is the case, post-CDC mutations could lead to a lesser dependence on antigen dependent BCR signaling and potentially a greater influence of off-target, non-IG genomic mutations. Alternatively, the latter activity could add a new stimulatory survival/growth advantage mediated by the BCR through structurally altered FRs, such as that occurring by superantigen binding and stimulation. Frontiers Media S.A. 2021-05-25 /pmc/articles/PMC8186829/ /pubmed/34113563 http://dx.doi.org/10.3389/fonc.2021.640731 Text en Copyright © 2021 Bagnara, Tang, Brown, Kasar, Fernandes, Colombo, Vergani, Mazzarello, Ghiotto, Bruno, Morabito, Rai, Kolitz, Barrientos, Allen, Fais, Scharff, MacCarthy and Chiorazzi 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
Bagnara, Davide
Tang, Catherine
Brown, Jennifer R.
Kasar, Siddha
Fernandes, Stacey
Colombo, Monica
Vergani, Stefano
Mazzarello, Andrea N.
Ghiotto, Fabio
Bruno, Silvia
Morabito, Fortunato
Rai, Kanti R.
Kolitz, Jonathan E.
Barrientos, Jacqueline C.
Allen, Steven L.
Fais, Franco
Scharff, Matthew D.
MacCarthy, Thomas
Chiorazzi, Nicholas
Post-Transformation IGHV-IGHD-IGHJ Mutations in Chronic Lymphocytic Leukemia B Cells: Implications for Mutational Mechanisms and Impact on Clinical Course
title Post-Transformation IGHV-IGHD-IGHJ Mutations in Chronic Lymphocytic Leukemia B Cells: Implications for Mutational Mechanisms and Impact on Clinical Course
title_full Post-Transformation IGHV-IGHD-IGHJ Mutations in Chronic Lymphocytic Leukemia B Cells: Implications for Mutational Mechanisms and Impact on Clinical Course
title_fullStr Post-Transformation IGHV-IGHD-IGHJ Mutations in Chronic Lymphocytic Leukemia B Cells: Implications for Mutational Mechanisms and Impact on Clinical Course
title_full_unstemmed Post-Transformation IGHV-IGHD-IGHJ Mutations in Chronic Lymphocytic Leukemia B Cells: Implications for Mutational Mechanisms and Impact on Clinical Course
title_short Post-Transformation IGHV-IGHD-IGHJ Mutations in Chronic Lymphocytic Leukemia B Cells: Implications for Mutational Mechanisms and Impact on Clinical Course
title_sort post-transformation ighv-ighd-ighj mutations in chronic lymphocytic leukemia b cells: implications for mutational mechanisms and impact on clinical course
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186829/
https://www.ncbi.nlm.nih.gov/pubmed/34113563
http://dx.doi.org/10.3389/fonc.2021.640731
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