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Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia

Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the...

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Autores principales: Kaufman, Matthew, Yan, Xiao-Jie, Li, Wentian, Ghia, Emanuela M., Langerak, Anton W., Rassenti, Laura Z., Belessi, Chrysoula, Kay, Neil E., Davi, Frederic, Byrd, John C., Pospisilova, Sarka, Brown, Jennifer R., Catherwood, Mark, Davis, Zadie, Oscier, David, Montillo, Marco, Trentin, Livio, Rosenquist, Richard, Ghia, Paolo, Barrientos, Jacqueline C., Kolitz, Jonathan E., Allen, Steven L., Rai, Kanti R., Stamatopoulos, Kostas, Kipps, Thomas J., Neuberg, Donna, Chiorazzi, Nicholas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9315922/
https://www.ncbi.nlm.nih.gov/pubmed/35903706
http://dx.doi.org/10.3389/fonc.2022.897280
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author Kaufman, Matthew
Yan, Xiao-Jie
Li, Wentian
Ghia, Emanuela M.
Langerak, Anton W.
Rassenti, Laura Z.
Belessi, Chrysoula
Kay, Neil E.
Davi, Frederic
Byrd, John C.
Pospisilova, Sarka
Brown, Jennifer R.
Catherwood, Mark
Davis, Zadie
Oscier, David
Montillo, Marco
Trentin, Livio
Rosenquist, Richard
Ghia, Paolo
Barrientos, Jacqueline C.
Kolitz, Jonathan E.
Allen, Steven L.
Rai, Kanti R.
Stamatopoulos, Kostas
Kipps, Thomas J.
Neuberg, Donna
Chiorazzi, Nicholas
author_facet Kaufman, Matthew
Yan, Xiao-Jie
Li, Wentian
Ghia, Emanuela M.
Langerak, Anton W.
Rassenti, Laura Z.
Belessi, Chrysoula
Kay, Neil E.
Davi, Frederic
Byrd, John C.
Pospisilova, Sarka
Brown, Jennifer R.
Catherwood, Mark
Davis, Zadie
Oscier, David
Montillo, Marco
Trentin, Livio
Rosenquist, Richard
Ghia, Paolo
Barrientos, Jacqueline C.
Kolitz, Jonathan E.
Allen, Steven L.
Rai, Kanti R.
Stamatopoulos, Kostas
Kipps, Thomas J.
Neuberg, Donna
Chiorazzi, Nicholas
author_sort Kaufman, Matthew
collection PubMed
description Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, “(S+Rc) to Rnc IGHV mutation ratio”. When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc ≤ 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question.
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spelling pubmed-93159222022-07-27 Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia Kaufman, Matthew Yan, Xiao-Jie Li, Wentian Ghia, Emanuela M. Langerak, Anton W. Rassenti, Laura Z. Belessi, Chrysoula Kay, Neil E. Davi, Frederic Byrd, John C. Pospisilova, Sarka Brown, Jennifer R. Catherwood, Mark Davis, Zadie Oscier, David Montillo, Marco Trentin, Livio Rosenquist, Richard Ghia, Paolo Barrientos, Jacqueline C. Kolitz, Jonathan E. Allen, Steven L. Rai, Kanti R. Stamatopoulos, Kostas Kipps, Thomas J. Neuberg, Donna Chiorazzi, Nicholas Front Oncol Oncology Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, “(S+Rc) to Rnc IGHV mutation ratio”. When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc ≤ 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question. Frontiers Media S.A. 2022-07-12 /pmc/articles/PMC9315922/ /pubmed/35903706 http://dx.doi.org/10.3389/fonc.2022.897280 Text en Copyright © 2022 Kaufman, Yan, Li, Ghia, Langerak, Rassenti, Belessi, Kay, Davi, Byrd, Pospisilova, Brown, Catherwood, Davis, Oscier, Montillo, Trentin, Rosenquist, Ghia, Barrientos, Kolitz, Allen, Rai, Stamatopoulos, Kipps, Neuberg 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
Kaufman, Matthew
Yan, Xiao-Jie
Li, Wentian
Ghia, Emanuela M.
Langerak, Anton W.
Rassenti, Laura Z.
Belessi, Chrysoula
Kay, Neil E.
Davi, Frederic
Byrd, John C.
Pospisilova, Sarka
Brown, Jennifer R.
Catherwood, Mark
Davis, Zadie
Oscier, David
Montillo, Marco
Trentin, Livio
Rosenquist, Richard
Ghia, Paolo
Barrientos, Jacqueline C.
Kolitz, Jonathan E.
Allen, Steven L.
Rai, Kanti R.
Stamatopoulos, Kostas
Kipps, Thomas J.
Neuberg, Donna
Chiorazzi, Nicholas
Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia
title Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia
title_full Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia
title_fullStr Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia
title_full_unstemmed Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia
title_short Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia
title_sort impact of the types and relative quantities of ighv gene mutations in predicting prognosis of patients with chronic lymphocytic leukemia
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9315922/
https://www.ncbi.nlm.nih.gov/pubmed/35903706
http://dx.doi.org/10.3389/fonc.2022.897280
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