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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.

SUBMITTER: Takam Kamga P

PROVIDER: S-EPMC6966525 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia.

Takam Kamga Paul P Dal Collo Giada G Resci Federica F Bazzoni Riccardo R Mercuri Angela A Quaglia Francesca Maria FM Tanasi Ilaria I Delfino Pietro P Visco Carlo C Bonifacio Massimiliano M Krampera Mauro M

Cancers 20191206 12

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 uni ...[more]

PMID: 31817634

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Project description:BackgroundAcute myeloid leukemia (AML) is the most common hematological malignancy in adult patients. Ferroptosis-related signatures have been shown to act as regulators of the progression of multiple cancer types, but the role of ferroptosis in AML remains to be elucidated. We performed the present study to preliminarily investigate the roles of ferroptosis-related genes (FRGs) in AML.MethodsThe transcriptome data of AML patients was downloaded from The Cancer Genome Atlas (TCGA) and the transcriptome data of normal samples was obtained from the Genotype-Tissue Expression (GTEx) database. FRGs were selected via public articles. Expression levels of FRGs between AML and normal samples were analyzed. The prognostic model based on FRGs was constructed via lasso regression. The expression levels and prognostic role of FRGs were identified from the risk model. We also performed validation experiments to verify the expression levels of the final selected genes via immunohistochemistry, polymerase chain reaction (PCR), and RNA-seq. Finally, we explored the associations between immune infiltration, drug sensitivity, and the selected FRGs.ResultsThe transcriptome data of 151 AML samples were retrieved from TCGA and 70 bone marrow normal samples were retrieved from the GTEx database. Additionally, 23 FRGs were collected from the published articles. There were 22 differentially expressed FRGs, and among them, dipetidyl peptidase-4 (DPP4) (P= 0.011, HR =1.504), GPX4 (P=0.055, HR =1.569), LPCAT3 (P<0.001, HR =2.243), SLC7A11 (P=0.012, HR =2.243), and transferrin receptor (TFRC) (P=0.029, 0.774) had a significant influence on the prognosis of AML patients via lasso regression. The area under the curve (AUC) values of the 1-, 3-, and 5-year receiver operating characteristic (ROC) curves of the FRG signatures indicated that this model is novel and effective method for predicting the prognosis of AML patients. DPP4 (P<0.001) was overexpressed while LPCAT3 (P<0.001), TFRC (P<0.001), GPX4 (P<0.001), and SLC7A11 (P<0.001) were downregulated, further validation experiment results indicated that DPP4 was significantly downregulated but TFRC was upregulated in AML samples. Dysregulation of DPP4 and TFRC influence numbers of chemotherapy regimens sensitivity.ConclusionsDPP4 and TFRC act as biomarkers for predicting and diagnosing AML, and their expression levels also have significant correlations with drug resistance in AML.

Dataset Information

Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia.

Publications

Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia.

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