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Notch signaling plays a critical role in embryonic vascular developmentand tumor angiogenesis. The present study was conducted to investigate the prognosticrole of the angiogenesis-related Notch ligand and the receptor in acute myeloidleukemia (AML) and assess whether their expression correlates with that of thevascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2. Bone marrowmononuclear cells from 60 untreated AML patients and 40 healthy controls wereobtained. Real-time RT-PCR was performed to evaluate the mRNA expression of δ-likeligand 4 (Dll4), Notch1, VEGF, VEGF receptor (VEGFR)-1, VEGFR-2, Ang-1, Ang-2and Tie2. Western blot analysis was used to determine the protein levels of Dll4and Notch1. The results demonstrated that Dll4, Notch1, VEGF, VEGFR-2 and Ang-2expression were significantly higher in untreated AML patients than in the controls.Univariate analysis of factors associated with the overall survival showed a significantlyshorter survival in patients with the unfavorable karyotype, higher Dll4 expression,higher Notch1 expression, higher VEGF expression or higher Ang-2 expression. Furthermore,multivariate analysis revealed that the karyotype and expression levels of Notch1,Dll4, VEGF and Ang-2 were independent prognostic factors for overall survival.Additionally, the prognostic value of Dll4 expression (but not Notch1) was moresignificant in the subgroup consisting of patients with intermediate-risk cytogenetics.Subgroup analysis showed that Notch1 and Dll4 expression levels had a prognosticimpact on patients with high VEGF or Ang-2 levels. Taken together, our data provideevidence that the activation of the Notch pathway may indicate an unfavorableprognosis in AML. In particular, Dll4 may be a relevant prognostic marker in intermediate-riskAML.

Prognostic impact of δ-like ligand 4 and Notch1 in acute myeloid leukemia