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

Zhang,Jingru; Ma,Daoxin; Ye,Jingjing; Zang,Shaolei; Lu,Fei; Yang,Meixiang; Qu,Xun; Sun,Xiulian; Ji,Chunyan

doi:10.3892/or.2012.1943

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

Authors:
- Jingru Zhang
- Daoxin Ma
- Jingjing Ye
- Shaolei Zang
- Fei Lu
- Meixiang Yang
- Xun Qu
- Xiulian Sun
- Chunyan Ji
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Affiliations: Department of Hematology, Qilu Hospital, Shandong University, Jinan, P.R. China, Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, P.R. China, National Key Laboratory of Otolaryngology, Qilu Hospital, Shandong University, Jinan, P.R. China
Published online on: July 31, 2012 https://doi.org/10.3892/or.2012.1943
Pages: 1503-1511

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Abstract

Notch signaling plays a critical role in embryonic vascular development and tumor angiogenesis. The present study was conducted to investigate the prognostic role of the angiogenesis-related Notch ligand and the receptor in acute myeloid leukemia (AML) and assess whether their expression correlates with that of the vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2. Bone marrow mononuclear cells from 60 untreated AML patients and 40 healthy controls were obtained. Real-time RT-PCR was performed to evaluate the mRNA expression of δ-like ligand 4 (Dll4), Notch1, VEGF, VEGF receptor (VEGFR)-1, VEGFR-2, Ang-1, Ang-2 and Tie2. Western blot analysis was used to determine the protein levels of Dll4 and Notch1. The results demonstrated that Dll4, Notch1, VEGF, VEGFR-2 and Ang-2 expression were significantly higher in untreated AML patients than in the controls. Univariate analysis of factors associated with the overall survival showed a significantly shorter 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 more significant in the subgroup consisting of patients with intermediate-risk cytogenetics. Subgroup analysis showed that Notch1 and Dll4 expression levels had a prognostic impact on patients with high VEGF or Ang-2 levels. Taken together, our data provide evidence that the activation of the Notch pathway may indicate an unfavorable prognosis in AML. In particular, Dll4 may be a relevant prognostic marker in intermediate-risk AML.

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