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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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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. |
format | Online Article Text |
id | pubmed-8187905 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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