Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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
_version_ 1784635481317703680
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
work_keys_str_mv AT fiorcaristefania notch2increasestheresistancetovenetoclaxinducedapoptosisinchroniclymphocyticleukemiabcellsbyinducingmcl1
AT maffeirossana notch2increasestheresistancetovenetoclaxinducedapoptosisinchroniclymphocyticleukemiabcellsbyinducingmcl1
AT ateneclaudiogiacinto notch2increasestheresistancetovenetoclaxinducedapoptosisinchroniclymphocyticleukemiabcellsbyinducingmcl1
AT mesininicolo notch2increasestheresistancetovenetoclaxinducedapoptosisinchroniclymphocyticleukemiabcellsbyinducingmcl1
AT maccaferrimonica notch2increasestheresistancetovenetoclaxinducedapoptosisinchroniclymphocyticleukemiabcellsbyinducingmcl1
AT leonardigiovanna notch2increasestheresistancetovenetoclaxinducedapoptosisinchroniclymphocyticleukemiabcellsbyinducingmcl1
AT martinellisilvia notch2increasestheresistancetovenetoclaxinducedapoptosisinchroniclymphocyticleukemiabcellsbyinducingmcl1
AT paoliniambra notch2increasestheresistancetovenetoclaxinducedapoptosisinchroniclymphocyticleukemiabcellsbyinducingmcl1
AT nasillovincenzo notch2increasestheresistancetovenetoclaxinducedapoptosisinchroniclymphocyticleukemiabcellsbyinducingmcl1
AT debbiagiulia notch2increasestheresistancetovenetoclaxinducedapoptosisinchroniclymphocyticleukemiabcellsbyinducingmcl1
AT potenzaleonardo notch2increasestheresistancetovenetoclaxinducedapoptosisinchroniclymphocyticleukemiabcellsbyinducingmcl1
AT luppimario notch2increasestheresistancetovenetoclaxinducedapoptosisinchroniclymphocyticleukemiabcellsbyinducingmcl1
AT marascaroberto notch2increasestheresistancetovenetoclaxinducedapoptosisinchroniclymphocyticleukemiabcellsbyinducingmcl1