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NOTCH1 Activation Negatively Impacts on Chronic Lymphocytic Leukemia Outcome and Is Not Correlated to the NOTCH1 and IGHV Mutational Status

NOTCH1 mutations and deregulated signal have been commonly found in chronic lymphocytic leukemia (CLL) patients. Whereas the impact of NOTCH1 mutations on clinical course of CLL has been widely studied, the prognostic role of NOTCH1 activation in CLL remains to be defined. Here, we analyzed the acti...

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Autores principales: Baldoni, Stefano, Del Papa, Beatrice, De Falco, Filomena, Dorillo, Erica, Sorrentino, Carlo, Rompietti, Chiara, Adamo, Francesco Maria, Nogarotto, Manuel, Cecchini, Debora, Mondani, Elena, Silva Barcelos, Estevao Carlos, Moretti, Lorenzo, Mameli, Maria Grazia, Fabi, Bianca, Sorcini, Daniele, Stella, Arianna, Giancola, Raffaella, Guardalupi, Francesco, Ulbar, Francesca, Plebani, Sara, Guarente, Valerio, Rosati, Emanuela, Di Nicola, Marta, Marchioni, Michele, Di Ianni, Mauro, Sportoletti, Paolo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187905/
https://www.ncbi.nlm.nih.gov/pubmed/34123837
http://dx.doi.org/10.3389/fonc.2021.668573
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author Baldoni, Stefano
Del Papa, Beatrice
De Falco, Filomena
Dorillo, Erica
Sorrentino, Carlo
Rompietti, Chiara
Adamo, Francesco Maria
Nogarotto, Manuel
Cecchini, Debora
Mondani, Elena
Silva Barcelos, Estevao Carlos
Moretti, Lorenzo
Mameli, Maria Grazia
Fabi, Bianca
Sorcini, Daniele
Stella, Arianna
Giancola, Raffaella
Guardalupi, Francesco
Ulbar, Francesca
Plebani, Sara
Guarente, Valerio
Rosati, Emanuela
Di Nicola, Marta
Marchioni, Michele
Di Ianni, Mauro
Sportoletti, Paolo
author_facet Baldoni, Stefano
Del Papa, Beatrice
De Falco, Filomena
Dorillo, Erica
Sorrentino, Carlo
Rompietti, Chiara
Adamo, Francesco Maria
Nogarotto, Manuel
Cecchini, Debora
Mondani, Elena
Silva Barcelos, Estevao Carlos
Moretti, Lorenzo
Mameli, Maria Grazia
Fabi, Bianca
Sorcini, Daniele
Stella, Arianna
Giancola, Raffaella
Guardalupi, Francesco
Ulbar, Francesca
Plebani, Sara
Guarente, Valerio
Rosati, Emanuela
Di Nicola, Marta
Marchioni, Michele
Di Ianni, Mauro
Sportoletti, Paolo
author_sort Baldoni, Stefano
collection PubMed
description NOTCH1 mutations and deregulated signal have been commonly found in chronic lymphocytic leukemia (CLL) patients. Whereas the impact of NOTCH1 mutations on clinical course of CLL has been widely studied, the prognostic role of NOTCH1 activation in CLL remains to be defined. Here, we analyzed the activation of NOTCH1/NOTCH2 (ICN1/ICN2) and the expression of JAGGED1 (JAG1) in 163 CLL patients and evaluated their impact on TTFT (Time To First Treatment) and OS (Overall Survival). NOTCH1 activation (ICN1+) was found in 120/163 (73.6%) patients. Among them, 63 (52.5%) were NOTCH1 mutated (ICN1+/mutated) and 57 (47.5%) were NOTCH1 wild type (ICN1+/WT). ICN1+ patients had a significant reduction of TTFT compared to ICN1-negative (ICN1−). In the absence of NOTCH1 mutations, we found that the ICN1+/WT group had a significantly reduced TTFT compared to ICN1− patients. The analysis of IGHV mutational status showed that the distribution of the mutated/unmutated IGHV pattern was similar in ICN1+/WT and ICN1− patients. Additionally, TTFT was significantly reduced in ICN1+/ICN2+ and ICN1+/JAG1+ patients compared to ICN1−/ICN2− and ICN1−/JAG1− groups. Our data revealed for the first time that NOTCH1 activation is a negative prognosticator in CLL and is not correlated to NOTCH1 and IGHV mutational status. Activation of NOTCH2 and JAGGED1 expression might also influence clinical outcomes in this group, indicating the need for further dedicated studies. The evaluation of different NOTCH network components might represent a new approach to refine CLL risk stratification.
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spelling pubmed-81879052021-06-10 NOTCH1 Activation Negatively Impacts on Chronic Lymphocytic Leukemia Outcome and Is Not Correlated to the NOTCH1 and IGHV Mutational Status Baldoni, Stefano Del Papa, Beatrice De Falco, Filomena Dorillo, Erica Sorrentino, Carlo Rompietti, Chiara Adamo, Francesco Maria Nogarotto, Manuel Cecchini, Debora Mondani, Elena Silva Barcelos, Estevao Carlos Moretti, Lorenzo Mameli, Maria Grazia Fabi, Bianca Sorcini, Daniele Stella, Arianna Giancola, Raffaella Guardalupi, Francesco Ulbar, Francesca Plebani, Sara Guarente, Valerio Rosati, Emanuela Di Nicola, Marta Marchioni, Michele Di Ianni, Mauro Sportoletti, Paolo Front Oncol Oncology NOTCH1 mutations and deregulated signal have been commonly found in chronic lymphocytic leukemia (CLL) patients. Whereas the impact of NOTCH1 mutations on clinical course of CLL has been widely studied, the prognostic role of NOTCH1 activation in CLL remains to be defined. Here, we analyzed the activation of NOTCH1/NOTCH2 (ICN1/ICN2) and the expression of JAGGED1 (JAG1) in 163 CLL patients and evaluated their impact on TTFT (Time To First Treatment) and OS (Overall Survival). NOTCH1 activation (ICN1+) was found in 120/163 (73.6%) patients. Among them, 63 (52.5%) were NOTCH1 mutated (ICN1+/mutated) and 57 (47.5%) were NOTCH1 wild type (ICN1+/WT). ICN1+ patients had a significant reduction of TTFT compared to ICN1-negative (ICN1−). In the absence of NOTCH1 mutations, we found that the ICN1+/WT group had a significantly reduced TTFT compared to ICN1− patients. The analysis of IGHV mutational status showed that the distribution of the mutated/unmutated IGHV pattern was similar in ICN1+/WT and ICN1− patients. Additionally, TTFT was significantly reduced in ICN1+/ICN2+ and ICN1+/JAG1+ patients compared to ICN1−/ICN2− and ICN1−/JAG1− groups. Our data revealed for the first time that NOTCH1 activation is a negative prognosticator in CLL and is not correlated to NOTCH1 and IGHV mutational status. Activation of NOTCH2 and JAGGED1 expression might also influence clinical outcomes in this group, indicating the need for further dedicated studies. The evaluation of different NOTCH network components might represent a new approach to refine CLL risk stratification. Frontiers Media S.A. 2021-05-26 /pmc/articles/PMC8187905/ /pubmed/34123837 http://dx.doi.org/10.3389/fonc.2021.668573 Text en Copyright © 2021 Baldoni, Del Papa, De Falco, Dorillo, Sorrentino, Rompietti, Adamo, Nogarotto, Cecchini, Mondani, Silva Barcelos, Moretti, Mameli, Fabi, Sorcini, Stella, Giancola, Guardalupi, Ulbar, Plebani, Guarente, Rosati, Di Nicola, Marchioni, Di Ianni and Sportoletti 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
Baldoni, Stefano
Del Papa, Beatrice
De Falco, Filomena
Dorillo, Erica
Sorrentino, Carlo
Rompietti, Chiara
Adamo, Francesco Maria
Nogarotto, Manuel
Cecchini, Debora
Mondani, Elena
Silva Barcelos, Estevao Carlos
Moretti, Lorenzo
Mameli, Maria Grazia
Fabi, Bianca
Sorcini, Daniele
Stella, Arianna
Giancola, Raffaella
Guardalupi, Francesco
Ulbar, Francesca
Plebani, Sara
Guarente, Valerio
Rosati, Emanuela
Di Nicola, Marta
Marchioni, Michele
Di Ianni, Mauro
Sportoletti, Paolo
NOTCH1 Activation Negatively Impacts on Chronic Lymphocytic Leukemia Outcome and Is Not Correlated to the NOTCH1 and IGHV Mutational Status
title NOTCH1 Activation Negatively Impacts on Chronic Lymphocytic Leukemia Outcome and Is Not Correlated to the NOTCH1 and IGHV Mutational Status
title_full NOTCH1 Activation Negatively Impacts on Chronic Lymphocytic Leukemia Outcome and Is Not Correlated to the NOTCH1 and IGHV Mutational Status
title_fullStr NOTCH1 Activation Negatively Impacts on Chronic Lymphocytic Leukemia Outcome and Is Not Correlated to the NOTCH1 and IGHV Mutational Status
title_full_unstemmed NOTCH1 Activation Negatively Impacts on Chronic Lymphocytic Leukemia Outcome and Is Not Correlated to the NOTCH1 and IGHV Mutational Status
title_short NOTCH1 Activation Negatively Impacts on Chronic Lymphocytic Leukemia Outcome and Is Not Correlated to the NOTCH1 and IGHV Mutational Status
title_sort notch1 activation negatively impacts on chronic lymphocytic leukemia outcome and is not correlated to the notch1 and ighv mutational status
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187905/
https://www.ncbi.nlm.nih.gov/pubmed/34123837
http://dx.doi.org/10.3389/fonc.2021.668573
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