Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia.

Paul Takam Kamga,Francesca Maria Quaglia,Federica Resci,Pietro Delfino,Mauro Krampera,Angela Mercuri,Massimiliano Bonifacio,Carlo Visco,Giada Dal Collo,Riccardo Bazzoni,Ilaria Tanasi

doi:10.3390/cancers11121958

Abstract

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.

Highlights

Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in adulthood, still incurable in most patients, with a 35–40% five-year overall survival (OS) rate for non-promyelocyticacute myeloid leukemia (AML) [1,2]
To determine whether Notch expression levels at the cell membrane of primary blast cells collected from AML patients at diagnosis were associated with patient outcome, we analyzed the Notch signaling expression in 79 AML samples (Table 1) and 18 CD34+ cell samples from healthy donors
Notch1, Notch2, Notch3, Notch4, Jagged1, Jagged 2, DLL-1, DLL-3, and DLL-4were expressed in 86%

Summary

Introduction

Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in adulthood, still incurable in most patients, with a 35–40% five-year overall survival (OS) rate for non-promyelocyticAML [1,2]. Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in adulthood, still incurable in most patients, with a 35–40% five-year overall survival (OS) rate for non-promyelocytic. Despite the decisive contribution of currents prognostic markers, all these combining approaches fail to tackle disease complexity and outcome [2,6,7]. Notch signaling is a developmental pathway consisting of four receptors (Notch1–4) and five ligands, including Jagged, Delta-like ligand 1, 3–4 (DLL-1, DLL3–4). The interaction between ligands and receptors induces the release of the intracellular part of the receptors, which acts in combination with transcriptional co-activators and induces expression of target genes [8]. The activation of the pathway has been first described in T-cell acute lymphoblastic leukemia (T-ALL), where more than 50%

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Conclusion