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Absence of Non-Canonical, Inhibitory MYD88 Splice Variants in B Cell Lymphomas Correlates With Sustained NF-κB Signaling

Gain-of-function mutations of the TLR adaptor and oncoprotein MyD88 drive B cell lymphomagenesis via sustained NF-κB activation. In myeloid cells, both short and sustained TLR activation and NF-κB activation lead to the induction of inhibitory MYD88 splice variants that restrain prolonged NF-κB acti...

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Autores principales: Cardona Gloria, Yamel, Bernhart, Stephan H., Fillinger, Sven, Wolz, Olaf-Oliver, Dickhöfer, Sabine, Admard, Jakob, Ossowski, Stephan, Nahnsen, Sven, Siebert, Reiner, Weber, Alexander N. R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215704/
https://www.ncbi.nlm.nih.gov/pubmed/34163463
http://dx.doi.org/10.3389/fimmu.2021.616451
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author Cardona Gloria, Yamel
Bernhart, Stephan H.
Fillinger, Sven
Wolz, Olaf-Oliver
Dickhöfer, Sabine
Admard, Jakob
Ossowski, Stephan
Nahnsen, Sven
Siebert, Reiner
Weber, Alexander N. R.
author_facet Cardona Gloria, Yamel
Bernhart, Stephan H.
Fillinger, Sven
Wolz, Olaf-Oliver
Dickhöfer, Sabine
Admard, Jakob
Ossowski, Stephan
Nahnsen, Sven
Siebert, Reiner
Weber, Alexander N. R.
author_sort Cardona Gloria, Yamel
collection PubMed
description Gain-of-function mutations of the TLR adaptor and oncoprotein MyD88 drive B cell lymphomagenesis via sustained NF-κB activation. In myeloid cells, both short and sustained TLR activation and NF-κB activation lead to the induction of inhibitory MYD88 splice variants that restrain prolonged NF-κB activation. We therefore sought to investigate whether such a negative feedback loop exists in B cells. Analyzing MYD88 splice variants in normal B cells and different primary B cell malignancies, we observed that MYD88 splice variants in transformed B cells are dominated by the canonical, strongly NF-κB-activating isoform of MYD88 and contain at least three novel, so far uncharacterized signaling-competent splice isoforms. Sustained TLR stimulation in B cells unexpectedly reinforces splicing of NF-κB-promoting, canonical isoforms rather than the ‘MyD88s’, a negative regulatory isoform reported to be typically induced by TLRs in myeloid cells. This suggests that an essential negative feedback loop restricting TLR signaling in myeloid cells at the level of alternative splicing, is missing in B cells when they undergo proliferation, rendering B cells vulnerable to sustained NF-κB activation and eventual lymphomagenesis. Our results uncover MYD88 alternative splicing as an unappreciated promoter of B cell lymphomagenesis and provide a rationale why oncogenic MYD88 mutations are exclusively found in B cells.
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spelling pubmed-82157042021-06-22 Absence of Non-Canonical, Inhibitory MYD88 Splice Variants in B Cell Lymphomas Correlates With Sustained NF-κB Signaling Cardona Gloria, Yamel Bernhart, Stephan H. Fillinger, Sven Wolz, Olaf-Oliver Dickhöfer, Sabine Admard, Jakob Ossowski, Stephan Nahnsen, Sven Siebert, Reiner Weber, Alexander N. R. Front Immunol Immunology Gain-of-function mutations of the TLR adaptor and oncoprotein MyD88 drive B cell lymphomagenesis via sustained NF-κB activation. In myeloid cells, both short and sustained TLR activation and NF-κB activation lead to the induction of inhibitory MYD88 splice variants that restrain prolonged NF-κB activation. We therefore sought to investigate whether such a negative feedback loop exists in B cells. Analyzing MYD88 splice variants in normal B cells and different primary B cell malignancies, we observed that MYD88 splice variants in transformed B cells are dominated by the canonical, strongly NF-κB-activating isoform of MYD88 and contain at least three novel, so far uncharacterized signaling-competent splice isoforms. Sustained TLR stimulation in B cells unexpectedly reinforces splicing of NF-κB-promoting, canonical isoforms rather than the ‘MyD88s’, a negative regulatory isoform reported to be typically induced by TLRs in myeloid cells. This suggests that an essential negative feedback loop restricting TLR signaling in myeloid cells at the level of alternative splicing, is missing in B cells when they undergo proliferation, rendering B cells vulnerable to sustained NF-κB activation and eventual lymphomagenesis. Our results uncover MYD88 alternative splicing as an unappreciated promoter of B cell lymphomagenesis and provide a rationale why oncogenic MYD88 mutations are exclusively found in B cells. Frontiers Media S.A. 2021-06-07 /pmc/articles/PMC8215704/ /pubmed/34163463 http://dx.doi.org/10.3389/fimmu.2021.616451 Text en Copyright © 2021 Cardona Gloria, Bernhart, Fillinger, Wolz, Dickhöfer, Admard, Ossowski, Nahnsen, Siebert and Weber 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 Immunology
Cardona Gloria, Yamel
Bernhart, Stephan H.
Fillinger, Sven
Wolz, Olaf-Oliver
Dickhöfer, Sabine
Admard, Jakob
Ossowski, Stephan
Nahnsen, Sven
Siebert, Reiner
Weber, Alexander N. R.
Absence of Non-Canonical, Inhibitory MYD88 Splice Variants in B Cell Lymphomas Correlates With Sustained NF-κB Signaling
title Absence of Non-Canonical, Inhibitory MYD88 Splice Variants in B Cell Lymphomas Correlates With Sustained NF-κB Signaling
title_full Absence of Non-Canonical, Inhibitory MYD88 Splice Variants in B Cell Lymphomas Correlates With Sustained NF-κB Signaling
title_fullStr Absence of Non-Canonical, Inhibitory MYD88 Splice Variants in B Cell Lymphomas Correlates With Sustained NF-κB Signaling
title_full_unstemmed Absence of Non-Canonical, Inhibitory MYD88 Splice Variants in B Cell Lymphomas Correlates With Sustained NF-κB Signaling
title_short Absence of Non-Canonical, Inhibitory MYD88 Splice Variants in B Cell Lymphomas Correlates With Sustained NF-κB Signaling
title_sort absence of non-canonical, inhibitory myd88 splice variants in b cell lymphomas correlates with sustained nf-κb signaling
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215704/
https://www.ncbi.nlm.nih.gov/pubmed/34163463
http://dx.doi.org/10.3389/fimmu.2021.616451
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