Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia

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.

The Role of Notch and Wnt Signaling in MSC Communication in Normal and Leukemic Bone Marrow Niche

“…Notably, in a recent study we found that less mature AML subtypes (M0-M1) expressed high levels of all the four receptors (Notch1–4) and some ligands (Jagged2, DLL-3), whereas adverse cytogenetic risk groups overexpressed Notch3, Notch4, and Jagged2 as compared to good cytogenetic risk patients. Accordingly, univariate and multivariate analysis confirmed a longer overall survival for patients presenting low expression of Notch4, Jagged2, and DLL3 on leukemia cells at diagnosis ( Takam Kamga et al, 2019a ).…”

“…Putting in the context of anti-leukemic treatment, epigenetic analysis of blast cells collected from B-ALL patients along the course of the disease revealed that the methylation pattern of Notch receptors’ genes changes according to the disease step. It was observed that Notch genes receptors are highly methylated at diagnosis, less methylated upon drug treatment and became hypermethylated in relapsed patients ( Takam Kamga et al, 2019a ). These observations suggested that the methylation status of Notch genes might be relevant for drug response.…”

“…In the study by Tohda and Nara (2001) 6 cell lines out of 8 and 40% of AML fresh samples showed active forms of Notch1 receptors. Some observations suggest that Notch expression and activation levels in AML could be correlated with the molecular background of each samples or the FAB subgroup ( Tohda and Nara, 2001 ; Salat et al, 2008 ; Grieselhuber et al, 2013 ; Sliwa et al, 2014 ; Czemerska et al, 2015 ; Takam Kamga et al, 2019a ). For example, ETO in association with RBP-jk inhibits the expression of Notch target genes, while the leukemogenic fusion protein AML1/ETO is devoid of this repressive activity ( Salat et al, 2008 ).…”

“… Grieselhuber et al (2013) identified Notch expression and activation in acute promyelocytic leukemia presenting the PML-RARα rearrangement. However, Notch pathway activation has been observed mostly in more immature AML subtypes and was associated with bad prognosis, as patients with hyper-expression of Notch1 displayed poorer overall survival ( Xu et al, 2011 ; Sliwa et al, 2014 ; Takam Kamga et al, 2019a ). Notably, in a recent study we found that less mature AML subtypes (M0-M1) expressed high levels of all the four receptors (Notch1–4) and some ligands (Jagged2, DLL-3), whereas adverse cytogenetic risk groups overexpressed Notch3, Notch4, and Jagged2 as compared to good cytogenetic risk patients.…”

Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives

“…Unlike T-ALL, activating NOTCH1 mutations in AML are rarely found; however, overexpression of Notch 1 and its ligands have been shown to be independent prognostic markers of overall patient survival [ 56 , 57 , 58 , 59 ]. In a recent AML study, Notch 3, 4 and Jagged-1 were associated with an adverse cytogeneic risk, Notch 2 and 3 expression were associated with increased relapse following induction therapy, Notch 4 and Jagged-2 were associated with increased relapse following allogeneic stem cell transplantation, while Notch 4, Jagged-2 and DLL-3 expression were associated with a poor OS in AML patients, further supporting the biomarker and therapeutic potential of Notch in this cancer [ 60 ].…”