Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia.

AML Notch signaling biomarkers

Journal

Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829

Informations de publication

Date de publication:
06 12 2019
Historique:
received: 31 10 2019
revised: 22 11 2019
accepted: 03 12 2019
entrez: 11 12 2019
pubmed: 11 12 2019
medline: 11 12 2019
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.3390/cancers11121958 PMID: 31817634 PMC: PMC6966525
pubmed: 31817634
pii: cancers11121958
doi: 10.3390/cancers11121958
pmc: PMC6966525
pii:
doi:

Types de publication

Journal Article

Langues

eng

Subventions

Organisme : Fondazione Cassa di Risparmio di Verona Vicenza Belluno e Ancona
ID : 2012
Pays : International

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Auteurs

Paul Takam Kamga (P)

Section of Hematology, Stem Cell Research Laboratory, Department of Medicine, University of Verona, Policlinico G.B. Rossi., P.le L. Scuro, 10, 37134 Verona, Italy.
EA4340-BCOH, Biomarker in Cancerology and Onco-Haematology, UVSQ, Université Paris Saclay, 92100 Boulogne-Billancourt, France.
ORCID: 0000-0002-8586-1381

Giada Dal Collo (G)

Section of Hematology, Stem Cell Research Laboratory, Department of Medicine, University of Verona, Policlinico G.B. Rossi., P.le L. Scuro, 10, 37134 Verona, Italy.
ORCID: 0000-0001-7348-370X

Federica Resci (F)

Section of Hematology, Stem Cell Research Laboratory, Department of Medicine, University of Verona, Policlinico G.B. Rossi., P.le L. Scuro, 10, 37134 Verona, Italy.

Riccardo Bazzoni (R)

Section of Hematology, Stem Cell Research Laboratory, Department of Medicine, University of Verona, Policlinico G.B. Rossi., P.le L. Scuro, 10, 37134 Verona, Italy.
ORCID: 0000-0002-5977-7178

Angela Mercuri (A)

Section of Hematology, Stem Cell Research Laboratory, Department of Medicine, University of Verona, Policlinico G.B. Rossi., P.le L. Scuro, 10, 37134 Verona, Italy.

Francesca Maria Quaglia (FM)

Section of Hematology, Stem Cell Research Laboratory, Department of Medicine, University of Verona, Policlinico G.B. Rossi., P.le L. Scuro, 10, 37134 Verona, Italy.

Ilaria Tanasi (I)

Section of Hematology, Stem Cell Research Laboratory, Department of Medicine, University of Verona, Policlinico G.B. Rossi., P.le L. Scuro, 10, 37134 Verona, Italy.

Pietro Delfino (P)

Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy.
ORCID: 0000-0003-0119-0830

Carlo Visco (C)

Section of Hematology, Stem Cell Research Laboratory, Department of Medicine, University of Verona, Policlinico G.B. Rossi., P.le L. Scuro, 10, 37134 Verona, Italy.

Massimiliano Bonifacio (M)

Section of Hematology, Stem Cell Research Laboratory, Department of Medicine, University of Verona, Policlinico G.B. Rossi., P.le L. Scuro, 10, 37134 Verona, Italy.
ORCID: 0000-0003-0716-1686

Mauro Krampera (M)

Section of Hematology, Stem Cell Research Laboratory, Department of Medicine, University of Verona, Policlinico G.B. Rossi., P.le L. Scuro, 10, 37134 Verona, Italy.

Classifications MeSH