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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Frontiers Media S.A.
2021-05-01
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Series: | Frontiers in Oncology |
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Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.668573/full |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Stefano Baldoni Stefano Baldoni Beatrice Del Papa Filomena De Falco Erica Dorillo Carlo Sorrentino Chiara Rompietti Francesco Maria Adamo Manuel Nogarotto Debora Cecchini Elena Mondani Estevao Carlos Silva Barcelos Estevao Carlos Silva Barcelos Lorenzo Moretti Maria Grazia Mameli Bianca Fabi Daniele Sorcini Arianna Stella Raffaella Giancola Francesco Guardalupi Francesca Ulbar Sara Plebani Valerio Guarente Emanuela Rosati Marta Di Nicola Michele Marchioni Mauro Di Ianni Mauro Di Ianni Paolo Sportoletti |
spellingShingle |
Stefano Baldoni Stefano Baldoni Beatrice Del Papa Filomena De Falco Erica Dorillo Carlo Sorrentino Chiara Rompietti Francesco Maria Adamo Manuel Nogarotto Debora Cecchini Elena Mondani Estevao Carlos Silva Barcelos Estevao Carlos Silva Barcelos Lorenzo Moretti Maria Grazia Mameli Bianca Fabi Daniele Sorcini Arianna Stella Raffaella Giancola Francesco Guardalupi Francesca Ulbar Sara Plebani Valerio Guarente Emanuela Rosati Marta Di Nicola Michele Marchioni Mauro Di Ianni Mauro Di Ianni Paolo Sportoletti NOTCH1 Activation Negatively Impacts on Chronic Lymphocytic Leukemia Outcome and Is Not Correlated to the NOTCH1 and IGHV Mutational Status Frontiers in Oncology risk stratification NOTCH1 activation chronic lymphocytic leukemia IGHV mutation NOTCH1 mutation |
author_facet |
Stefano Baldoni Stefano Baldoni Beatrice Del Papa Filomena De Falco Erica Dorillo Carlo Sorrentino Chiara Rompietti Francesco Maria Adamo Manuel Nogarotto Debora Cecchini Elena Mondani Estevao Carlos Silva Barcelos Estevao Carlos Silva Barcelos Lorenzo Moretti Maria Grazia Mameli Bianca Fabi Daniele Sorcini Arianna Stella Raffaella Giancola Francesco Guardalupi Francesca Ulbar Sara Plebani Valerio Guarente Emanuela Rosati Marta Di Nicola Michele Marchioni Mauro Di Ianni Mauro Di Ianni Paolo Sportoletti |
author_sort |
Stefano Baldoni |
title |
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_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_sort |
notch1 activation negatively impacts on chronic lymphocytic leukemia outcome and is not correlated to the notch1 and ighv mutational status |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2021-05-01 |
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. |
topic |
risk stratification NOTCH1 activation chronic lymphocytic leukemia IGHV mutation NOTCH1 mutation |
url |
https://www.frontiersin.org/articles/10.3389/fonc.2021.668573/full |
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doaj-bf604ad42c61485b9c589e15303f68992021-05-26T06:42:34ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-05-011110.3389/fonc.2021.668573668573NOTCH1 Activation Negatively Impacts on Chronic Lymphocytic Leukemia Outcome and Is Not Correlated to the NOTCH1 and IGHV Mutational StatusStefano Baldoni0Stefano Baldoni1Beatrice Del Papa2Filomena De Falco3Erica Dorillo4Carlo Sorrentino5Chiara Rompietti6Francesco Maria Adamo7Manuel Nogarotto8Debora Cecchini9Elena Mondani10Estevao Carlos Silva Barcelos11Estevao Carlos Silva Barcelos12Lorenzo Moretti13Maria Grazia Mameli14Bianca Fabi15Daniele Sorcini16Arianna Stella17Raffaella Giancola18Francesco Guardalupi19Francesca Ulbar20Sara Plebani21Valerio Guarente22Emanuela Rosati23Marta Di Nicola24Michele Marchioni25Mauro Di Ianni26Mauro Di Ianni27Paolo Sportoletti28Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyDepartment of Medicine and Aging Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti, ItalyInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyDepartment of Medicine and Aging Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti, ItalyInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyDepartment of Biological Sciences, Postgraduate Program in Biotechnology (UFES), Federal University of Espirito Santo, Vitoria, BrazilInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyDepartment of Medicine and Aging Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti, ItalyInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyDepartment of Oncology and Hematology, “Santo Spirito” Hospital, Pescara, ItalyDepartment of Medicine and Aging Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti, ItalyDepartment of Medicine and Aging Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti, ItalyHematology Unit, “San Salvatore” Hospital, L’Aquila, ItalyInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyDepartment of Medicine and Surgery, University of Perugia, Perugia, ItalyDepartment of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti, ItalyDepartment of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti, ItalyDepartment of Medicine and Aging Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti, ItalyDepartment of Oncology and Hematology, “Santo Spirito” Hospital, Pescara, ItalyInstitute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, ItalyNOTCH1 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.https://www.frontiersin.org/articles/10.3389/fonc.2021.668573/fullrisk stratificationNOTCH1 activationchronic lymphocytic leukemiaIGHV mutationNOTCH1 mutation |