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

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.

Expression of Notch-1 and its clinical significance in different histological subtypes of human lung adenocarcinoma

“…Notch-1 was first found to associate with hematological diseases, and its expression level increased in multiple myeloma, Hodgkin’s lymphoma, anaplastic large cell lymphoma and acute myeloid leukemia [13,14]. Recently, Notch-1 was widely studied and reported to aberrantly express in malignant tumors [15-19].…”

Tumor Suppressor DYRK1A Effects on Proliferation and Chemoresistance of AML Cells by Downregulating c-Myc

“…Reverse transcription was performed using M-MLV reverse transcriptase cDNA Synthesis Kit(Takara, Japan). Real-time RT-PCR was carried out on ABI 7900HT Fast Real-Time PCR System(Foster City, CA) with SYBR-Green PCR Master Mix (Toyobo, Japan) as described previously[20]. Melting curves analysis and agarose gel electrophoresis were applied to guarantee the specificity of amplification.…”

Genomic architecture and treatment outcome in pediatric acute myeloid leukemia: a Children’s Oncology Group report

“…27 Two studies showed that DLL4 and NOTCH1 expression was significantly higher in patients with AML than in controls, indicating that activation of NOTCH signaling may promote AML development and be associated with an unfavorable prognosis. 28,29 Also at this breakpoint is MLLT4 (AF6), the partner of MLL in t(6;11)(q27;q23) translocation. Lastly, the 17q24 region identified with a focal gain contains TK1, an enzyme involved in nucleic acid synthesis.…”