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Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia

The role of Notch signaling in acute myeloid leukemia (AML) is still under investigation. We have previously shown that high levels of Notch receptors and ligands could interfere with drug response. In this study, the protein expression of 79 AML blast samples collected from newly diagnosed patients...

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Autores principales: Takam Kamga, Paul, Collo, Giada Dal, Resci, Federica, Bazzoni, Riccardo, Mercuri, Angela, Quaglia, Francesca Maria, Tanasi, Ilaria, Delfino, Pietro, Visco, Carlo, Bonifacio, Massimiliano, Krampera, Mauro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966525/
https://www.ncbi.nlm.nih.gov/pubmed/31817634
http://dx.doi.org/10.3390/cancers11121958
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author Takam Kamga, Paul
Collo, Giada Dal
Resci, Federica
Bazzoni, Riccardo
Mercuri, Angela
Quaglia, Francesca Maria
Tanasi, Ilaria
Delfino, Pietro
Visco, Carlo
Bonifacio, Massimiliano
Krampera, Mauro
author_facet Takam Kamga, Paul
Collo, Giada Dal
Resci, Federica
Bazzoni, Riccardo
Mercuri, Angela
Quaglia, Francesca Maria
Tanasi, Ilaria
Delfino, Pietro
Visco, Carlo
Bonifacio, Massimiliano
Krampera, Mauro
author_sort Takam Kamga, Paul
collection PubMed
description The role of Notch signaling in acute myeloid leukemia (AML) is still under investigation. We have previously shown that high levels of Notch receptors and ligands could interfere with drug response. In this study, the protein expression of 79 AML blast samples collected from newly diagnosed patients was examined through flow cytometry. Gamma-secretase inhibitors were used in AML mouse xenograft models to evaluate the contribution of Notch pharmacological inhibition to mouse survival. We used univariate analysis for testing the correlation and/or association between protein expression and well-known prognostics markers. All the four receptors (Notch1–4) and some ligands (Jagged2, DLL-3) were highly expressed in less mature subtypes (M0–M1). Notch3, Notch4, and Jagged2 were overexpressed in an adverse cytogenetic risk group compared to good cytogenetic risk patients. Chi-square analysis revealed a positive association between the complete remission rate after induction therapy and weak expression of Notch2 and Notch3. We also found an association between low levels of Notch4 and Jagged2 and three-year remission following allogeneic stem cell transplantation (HSCT). Accordingly, Kaplan–Meier analysis showed improved OS for patients lacking significant expression of Notch4, Jagged2, and DLL3. In vivo experiments in an AML mouse model highlighted both improved survival and a significant reduction of leukemia cell burden in the bone marrow of mice treated with the combination of Notch pan-inhibitors (GSIs) plus chemotherapy (Ara-C). Our results suggest that Notch can be useful as a prognostic marker and therapeutic target in AML.
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spelling pubmed-69665252020-01-27 Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia Takam Kamga, Paul Collo, Giada Dal Resci, Federica Bazzoni, Riccardo Mercuri, Angela Quaglia, Francesca Maria Tanasi, Ilaria Delfino, Pietro Visco, Carlo Bonifacio, Massimiliano Krampera, Mauro Cancers (Basel) Article The role of Notch signaling in acute myeloid leukemia (AML) is still under investigation. We have previously shown that high levels of Notch receptors and ligands could interfere with drug response. In this study, the protein expression of 79 AML blast samples collected from newly diagnosed patients was examined through flow cytometry. Gamma-secretase inhibitors were used in AML mouse xenograft models to evaluate the contribution of Notch pharmacological inhibition to mouse survival. We used univariate analysis for testing the correlation and/or association between protein expression and well-known prognostics markers. All the four receptors (Notch1–4) and some ligands (Jagged2, DLL-3) were highly expressed in less mature subtypes (M0–M1). Notch3, Notch4, and Jagged2 were overexpressed in an adverse cytogenetic risk group compared to good cytogenetic risk patients. Chi-square analysis revealed a positive association between the complete remission rate after induction therapy and weak expression of Notch2 and Notch3. We also found an association between low levels of Notch4 and Jagged2 and three-year remission following allogeneic stem cell transplantation (HSCT). Accordingly, Kaplan–Meier analysis showed improved OS for patients lacking significant expression of Notch4, Jagged2, and DLL3. In vivo experiments in an AML mouse model highlighted both improved survival and a significant reduction of leukemia cell burden in the bone marrow of mice treated with the combination of Notch pan-inhibitors (GSIs) plus chemotherapy (Ara-C). Our results suggest that Notch can be useful as a prognostic marker and therapeutic target in AML. MDPI 2019-12-06 /pmc/articles/PMC6966525/ /pubmed/31817634 http://dx.doi.org/10.3390/cancers11121958 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Takam Kamga, Paul
Collo, Giada Dal
Resci, Federica
Bazzoni, Riccardo
Mercuri, Angela
Quaglia, Francesca Maria
Tanasi, Ilaria
Delfino, Pietro
Visco, Carlo
Bonifacio, Massimiliano
Krampera, Mauro
Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia
title Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia
title_full Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia
title_fullStr Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia
title_full_unstemmed Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia
title_short Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia
title_sort notch signaling molecules as prognostic biomarkers for acute myeloid leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966525/
https://www.ncbi.nlm.nih.gov/pubmed/31817634
http://dx.doi.org/10.3390/cancers11121958
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