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Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia
Paul Takam Kamga1,2, Giada Dal Collo1, Federica Resci1
1Section of Hematology, Stem Cell Research Laboratory, Department of Medicine, University of Verona, Policlinico G.B. Rossi., P.le L. Scuro, 10, 37134 Verona, Italy.
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.
Insights
Notch signaling plays a role in acute myeloid leukemia (AML) drug response. Inhibiting Notch signaling improved survival and reduced leukemia burden in AML mouse models, suggesting its potential as a therapeutic target.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- The role of Notch signaling in acute myeloid leukemia (AML) pathogenesis and treatment response remains incompletely understood.
- Previous research indicated that elevated Notch receptors and ligands can negatively impact drug efficacy in AML.
Purpose of the Study:
- To investigate the protein expression of Notch pathway components in newly diagnosed AML patient samples.
- To evaluate the therapeutic potential of inhibiting Notch signaling in AML, both as a monotherapy and in combination with chemotherapy.
Main Methods:
- Flow cytometry was employed to analyze the protein expression of Notch receptors (Notch1-4) and ligands (Jagged2, DLL-3) in 79 AML patient samples.
- Univariate analysis and Chi-square tests were used to correlate protein expression with clinical prognostic markers and remission rates.
- Pharmacological inhibition of Notch signaling using gamma-secretase inhibitors (GSIs) was assessed in AML mouse xenograft models, combined with chemotherapy (Ara-C).
Main Results:
- High expression of Notch receptors and ligands (Jagged2, DLL-3) was observed in less mature AML subtypes (M0-M1).
- Overexpression of Notch3, Notch4, and Jagged2 correlated with adverse cytogenetic risk.
- Weak expression of Notch2 and Notch3 was associated with higher complete remission rates, while low Notch4 and Jagged2 levels correlated with longer three-year remission post-allogeneic stem cell transplantation (HSCT).
- Kaplan-Meier analysis indicated improved overall survival (OS) in patients with low expression of Notch4, Jagged2, and DLL3.
- In vivo studies demonstrated that combined GSI and Ara-C treatment significantly improved mouse survival and reduced bone marrow leukemia burden.
Conclusions:
- Notch signaling components are differentially expressed in AML subtypes and correlate with clinical outcomes and cytogenetic risk.
- Notch pathway inhibition, particularly in combination with chemotherapy, shows promise for improving survival in AML.
- Notch pathway proteins represent potential prognostic markers and therapeutic targets for acute myeloid leukemia.
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