Activation of Notch signal pathway is associated with a poorer prognosis in acute myeloid leukemia

Abstract

Notch signal pathway plays a fundamental role in regulating haematopoietic development. It is also an important mediator of growth and survival in several cancer types, with Notch pathway genes functioning as oncogenes or tumor suppressors in different cancers. However, the clinical role of Notch signal pathway in acute myeloid leukemia (AML) remains unclear. To address this problem, we investigated the gene expression levels of Notch signal pathway members (Notch1, Jagged1 and Delta1) in bone marrow mononuclear cells by real-time quantitative PCR in a cohort of 100 patients with newly diagnosed de novo AML and normal marrow donors. The prognostic values of the three molecules in AML were also analyzed. Comparing with the normal controls, we show the transcriptional up-regulation of Notch1, Jagged1 and Delta1 in the bone marrow of AML patients with statistic differences (P = 0.008, 0.01 and 0.01, respectively). In addition, univariate analysis of factors associated with relapse-free survival and overall survival showed a significantly shorter survival in the patients with unfavorable karyotype, higher Notch1 expression, higher Jagged1 expression, or higher Delta1 expression. Moreover, Cox proportional hazards multivariate analysis of the univariate predictors identified karyotype and gene expression levels of Notch1, Jagged1 and Delta1 as independent prognostic factors for relapse-free survival and overall survival. Furthermore, the prognostic significance of Notch1, Jagged1 and Delta1 expression was more obvious in the subgroup of patients with intermediate-risk cytogenetics. Taken together, our data suggest for the first time that the activation of Notch pathway may indicate a poor prognosis in AML. Especially, Notch1, Jagged1 and Delta1 expression may be relevant prognostic markers in intermediate risk AML.