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Regulation of Bcl-XL by non-canonical NF-κB in the context of CD40-induced drug resistance in CLL
In chronic lymphocytic leukemia (CLL), the lymph node (LN) microenvironment delivers critical survival signals by inducing the expression of anti-apoptotic Bcl-2 members Bcl-XL, Bfl-1, and Mcl-1, resulting in apoptosis blockade. We determined previously that resistance against various drugs, among w...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167103/ https://www.ncbi.nlm.nih.gov/pubmed/33495554 http://dx.doi.org/10.1038/s41418-020-00692-w |
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author | Haselager, Marco Thijssen, Rachel West, Christopher Young, Louise Van Kampen, Roel Willmore, Elaine Mackay, Simon Kater, Arnon Eldering, Eric |
author_facet | Haselager, Marco Thijssen, Rachel West, Christopher Young, Louise Van Kampen, Roel Willmore, Elaine Mackay, Simon Kater, Arnon Eldering, Eric |
author_sort | Haselager, Marco |
collection | PubMed |
description | In chronic lymphocytic leukemia (CLL), the lymph node (LN) microenvironment delivers critical survival signals by inducing the expression of anti-apoptotic Bcl-2 members Bcl-XL, Bfl-1, and Mcl-1, resulting in apoptosis blockade. We determined previously that resistance against various drugs, among which is the clinically applied BH3 mimetic venetoclax, is dominated by upregulation of the anti-apoptotic regulator Bcl-XL. Direct clinical targeting of Bcl-XL by, e.g., Navitoclax is however not desirable due to induction of thrombocytopenia. Since the actual regulation of Bcl-XL in CLL in the context of the LN microenvironment is not well elucidated, we investigated various candidate LN signals to drive Bcl-XL expression. We found a dominance for NF-κB signaling upon CD40 stimulation, which results in activation of both the canonical and non-canonical NF-κB signaling pathways. We demonstrate that expression of Bcl-XL is first induced by the canonical NF-κB pathway, and subsequently boosted and continued via non-canonical NF-κB signaling through stabilization of NIK. NF-κB subunits p65 and p52 can both bind to the Bcl-XL promoter and activate transcription upon CD40 stimulation. Moreover, canonical NF-κB signaling was correlated with Bfl-1 expression, whereas Mcl-1 in contrast, was not transcriptionally regulated by NF-κB. Finally, we applied a novel compound targeting NIK to selectively inhibit the non-canonical NF-κB pathway and showed that venetoclax-resistant CLL cells were sensitized to venetoclax. In conclusion, protective signals from the CLL microenvironment can be tipped towards apoptosis sensitivity by interfering with non-canonical NF-κB signaling. |
format | Online Article Text |
id | pubmed-8167103 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81671032021-06-07 Regulation of Bcl-XL by non-canonical NF-κB in the context of CD40-induced drug resistance in CLL Haselager, Marco Thijssen, Rachel West, Christopher Young, Louise Van Kampen, Roel Willmore, Elaine Mackay, Simon Kater, Arnon Eldering, Eric Cell Death Differ Article In chronic lymphocytic leukemia (CLL), the lymph node (LN) microenvironment delivers critical survival signals by inducing the expression of anti-apoptotic Bcl-2 members Bcl-XL, Bfl-1, and Mcl-1, resulting in apoptosis blockade. We determined previously that resistance against various drugs, among which is the clinically applied BH3 mimetic venetoclax, is dominated by upregulation of the anti-apoptotic regulator Bcl-XL. Direct clinical targeting of Bcl-XL by, e.g., Navitoclax is however not desirable due to induction of thrombocytopenia. Since the actual regulation of Bcl-XL in CLL in the context of the LN microenvironment is not well elucidated, we investigated various candidate LN signals to drive Bcl-XL expression. We found a dominance for NF-κB signaling upon CD40 stimulation, which results in activation of both the canonical and non-canonical NF-κB signaling pathways. We demonstrate that expression of Bcl-XL is first induced by the canonical NF-κB pathway, and subsequently boosted and continued via non-canonical NF-κB signaling through stabilization of NIK. NF-κB subunits p65 and p52 can both bind to the Bcl-XL promoter and activate transcription upon CD40 stimulation. Moreover, canonical NF-κB signaling was correlated with Bfl-1 expression, whereas Mcl-1 in contrast, was not transcriptionally regulated by NF-κB. Finally, we applied a novel compound targeting NIK to selectively inhibit the non-canonical NF-κB pathway and showed that venetoclax-resistant CLL cells were sensitized to venetoclax. In conclusion, protective signals from the CLL microenvironment can be tipped towards apoptosis sensitivity by interfering with non-canonical NF-κB signaling. Nature Publishing Group UK 2021-01-25 2021-05 /pmc/articles/PMC8167103/ /pubmed/33495554 http://dx.doi.org/10.1038/s41418-020-00692-w Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Haselager, Marco Thijssen, Rachel West, Christopher Young, Louise Van Kampen, Roel Willmore, Elaine Mackay, Simon Kater, Arnon Eldering, Eric Regulation of Bcl-XL by non-canonical NF-κB in the context of CD40-induced drug resistance in CLL |
title | Regulation of Bcl-XL by non-canonical NF-κB in the context of CD40-induced drug resistance in CLL |
title_full | Regulation of Bcl-XL by non-canonical NF-κB in the context of CD40-induced drug resistance in CLL |
title_fullStr | Regulation of Bcl-XL by non-canonical NF-κB in the context of CD40-induced drug resistance in CLL |
title_full_unstemmed | Regulation of Bcl-XL by non-canonical NF-κB in the context of CD40-induced drug resistance in CLL |
title_short | Regulation of Bcl-XL by non-canonical NF-κB in the context of CD40-induced drug resistance in CLL |
title_sort | regulation of bcl-xl by non-canonical nf-κb in the context of cd40-induced drug resistance in cll |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167103/ https://www.ncbi.nlm.nih.gov/pubmed/33495554 http://dx.doi.org/10.1038/s41418-020-00692-w |
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