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Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1
Chronic lymphocytic leukemia (CLL) has experienced a clinical revolution—thanks to the discovery of crucial pathogenic mechanisms. CLL is still an incurable disease due to intrinsic or acquired resistance of the leukemic clone. Venetoclax is a Bcl-2 inhibitor with a marked activity in CLL, but emerg...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770925/ https://www.ncbi.nlm.nih.gov/pubmed/35070982 http://dx.doi.org/10.3389/fonc.2021.777587 |
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author | Fiorcari, Stefania Maffei, Rossana Atene, Claudio Giacinto Mesini, Nicolò Maccaferri, Monica Leonardi, Giovanna Martinelli, Silvia Paolini, Ambra Nasillo, Vincenzo Debbia, Giulia Potenza, Leonardo Luppi, Mario Marasca, Roberto |
author_facet | Fiorcari, Stefania Maffei, Rossana Atene, Claudio Giacinto Mesini, Nicolò Maccaferri, Monica Leonardi, Giovanna Martinelli, Silvia Paolini, Ambra Nasillo, Vincenzo Debbia, Giulia Potenza, Leonardo Luppi, Mario Marasca, Roberto |
author_sort | Fiorcari, Stefania |
collection | PubMed |
description | Chronic lymphocytic leukemia (CLL) has experienced a clinical revolution—thanks to the discovery of crucial pathogenic mechanisms. CLL is still an incurable disease due to intrinsic or acquired resistance of the leukemic clone. Venetoclax is a Bcl-2 inhibitor with a marked activity in CLL, but emerging patterns of resistance are being described. We hypothesize that intrinsic features of CLL cells may contribute to drive mechanisms of resistance to venetoclax. We analyzed the expression of Interferon Regulatory Factor 4 (IRF4), Notch2, and Mcl-1 in a cohort of CLL patients. We evaluated CLL cell viability after genetic and pharmaceutical modulation of Notch2 expression in patients harboring trisomy 12. We tested venetoclax in trisomy 12 CLL cells either silenced or not for Notch2 expression or in combination with an inhibitor of Mcl-1, AMG-176. Trisomy 12 CLL cells were characterized by low expression of IRF4 associated with high levels of Notch2 and Mcl-1. Notch2 and Mcl-1 expression determined protection of CLL cells from spontaneous and drug-induced apoptosis. Considering the involvement of Mcl-1 in venetoclax resistance, our data demonstrated a contribution of high levels of Notch2 and Mcl-1 in a reduced response to venetoclax in CLL cells carrying trisomy 12. Furthermore, reduction of Mcl-1 expression by silencing Notch2 or by treatment with AMG-176 was able to restore the response of CLL cells to venetoclax. The expression of Notch2 identifies a subset of CLL patients, mainly harboring trisomy 12, characterized by high levels of Mcl-1. This biological mechanism may compromise an effective response to venetoclax. |
format | Online Article Text |
id | pubmed-8770925 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-87709252022-01-21 Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1 Fiorcari, Stefania Maffei, Rossana Atene, Claudio Giacinto Mesini, Nicolò Maccaferri, Monica Leonardi, Giovanna Martinelli, Silvia Paolini, Ambra Nasillo, Vincenzo Debbia, Giulia Potenza, Leonardo Luppi, Mario Marasca, Roberto Front Oncol Oncology Chronic lymphocytic leukemia (CLL) has experienced a clinical revolution—thanks to the discovery of crucial pathogenic mechanisms. CLL is still an incurable disease due to intrinsic or acquired resistance of the leukemic clone. Venetoclax is a Bcl-2 inhibitor with a marked activity in CLL, but emerging patterns of resistance are being described. We hypothesize that intrinsic features of CLL cells may contribute to drive mechanisms of resistance to venetoclax. We analyzed the expression of Interferon Regulatory Factor 4 (IRF4), Notch2, and Mcl-1 in a cohort of CLL patients. We evaluated CLL cell viability after genetic and pharmaceutical modulation of Notch2 expression in patients harboring trisomy 12. We tested venetoclax in trisomy 12 CLL cells either silenced or not for Notch2 expression or in combination with an inhibitor of Mcl-1, AMG-176. Trisomy 12 CLL cells were characterized by low expression of IRF4 associated with high levels of Notch2 and Mcl-1. Notch2 and Mcl-1 expression determined protection of CLL cells from spontaneous and drug-induced apoptosis. Considering the involvement of Mcl-1 in venetoclax resistance, our data demonstrated a contribution of high levels of Notch2 and Mcl-1 in a reduced response to venetoclax in CLL cells carrying trisomy 12. Furthermore, reduction of Mcl-1 expression by silencing Notch2 or by treatment with AMG-176 was able to restore the response of CLL cells to venetoclax. The expression of Notch2 identifies a subset of CLL patients, mainly harboring trisomy 12, characterized by high levels of Mcl-1. This biological mechanism may compromise an effective response to venetoclax. Frontiers Media S.A. 2022-01-06 /pmc/articles/PMC8770925/ /pubmed/35070982 http://dx.doi.org/10.3389/fonc.2021.777587 Text en Copyright © 2022 Fiorcari, Maffei, Atene, Mesini, Maccaferri, Leonardi, Martinelli, Paolini, Nasillo, Debbia, Potenza, Luppi and Marasca 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 Fiorcari, Stefania Maffei, Rossana Atene, Claudio Giacinto Mesini, Nicolò Maccaferri, Monica Leonardi, Giovanna Martinelli, Silvia Paolini, Ambra Nasillo, Vincenzo Debbia, Giulia Potenza, Leonardo Luppi, Mario Marasca, Roberto Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1 |
title | Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1 |
title_full | Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1 |
title_fullStr | Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1 |
title_full_unstemmed | Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1 |
title_short | Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1 |
title_sort | notch2 increases the resistance to venetoclax-induced apoptosis in chronic lymphocytic leukemia b cells by inducing mcl-1 |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770925/ https://www.ncbi.nlm.nih.gov/pubmed/35070982 http://dx.doi.org/10.3389/fonc.2021.777587 |
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