Clinical Implication Of SCIN Expression And Promoter Methylation In Myeloid Malignancies

Objective: The gene SCIN was firstly reported in the megakaryocytic leukemia cell lines.The researchers found that this gene had the function of inducing differentiation,maturation and apoptosis,and inhibiting proliferation and tumorigenesis in megakaryocytic leukemia cell lines;however,the followed researchers discovered that this gene has the role of promoting tumorigenesis in several solid tumors.Based on the differences in the function of this gene among hematologic malignancy cell lines and solid tumors,and no related reports achieved about this gene in patients with hematologic malignancy,we have detected the expression as well as promoter methylation levels of gene SCIN in acute myeloid leukemia(AML),chronic myeloid leukemia(CML),and myelodysplastic syndrome(MDS)patients for futher exploring its clinical relevance.Methods: Real-time quantitative PCR was used to detect the expression of SCIN in 37 cases of controls,119 cases of newly diagnosed AML,13 cases of complete remission(CR)AML,64 cases of CML and 35 cases of MDS.Real-time quantitative methylation-specific PCR,combined with bisulphite sequencing PCR,was used to detect gene SCIN promoter methylation levels in 29 controls,103 AML patients,65 CML patients,and 75 MDS patients.Demethylated drug(5-aza-2'-deoxycytidine,5-aza-dC)was used to treat the THP1 leukemia cell line for exploring the funtions of gene SCIN promoter methylation in regulating its gene expression.Results: Compared with the control group,the expression level of gene SCIN was significantly down-regulated in AML patients(P=0.001),while the promoter methylation level was significantly up-regulated(P=0.001).The receiver operating characteristic curve(ROC)analysis showed that gene SCIN expression and promoter methylation levels have the ability to distinguish AML patients from controls(P=0.001 and P<0.001).AML patients were divided into SCIN low-expression group and SCIN high-expression group by using the cut-off value of ROC curve,and clinical parameters and prognosis were compared between the two groups.Patients with low SCIN expression were older than those with high SCIN expression(P=0.039),and the frequency of gene C/EBPA mutation was lower in patients with low SCIN expression than those with high SCIN expression(P=0.038).Compared with patients with high expression of SCIN,the CR rate of patients with low SCIN expression was significantly lower(P=0.009).Kaplan-Meier survival analysis showed that the overall survival time of patients with low SCIN expression was significantly reduced(P=0.036).Cox regression analysis showed that the gene SCIN expression was a factor that independently affects the prognosis of AML patients.Using the cut-off value of 0.113,AML patients were divided into SCIN hypermethylation group and SCIN hypomethylation group.Compared with patients in SCIN hypomethylation group,the proportion of bone marrow blast cells in patients with SCIN hypermethylation was increased(P=0.049).The frequency of gene N/K-RAS mutations was increased(P=0.026)in patients with SCIN hypermethylation.Spearman correlation analysis showed that the expression of SCIN was negatively correlated with promoter methylation in AML(R=-0.265,P=0.027),and the expression level of SCIN was increased in demethylated leukemic cells(P<0.05).For CML patients,the expression level of SCIN gene was significantly down-regulated compared with the controls(P=0.010);Spearman correlation analysis showed that the expression of gene SCIN was negatively correlated with the transcription level of BCR-ABL(R=-0.315,P=0.042).The expression levels of SCIN in MDS patients was significantly lower than those in the controls(P=0.029).Conclusions: Down-regulation of SCIN expression is a common molecular biological event in hematologic malignancy.The low expression of gene SCIN in AML patients is associated with a poor prognosis,and can be used to monitor the response with induction therapy.In AML patients,gene SCIN expression was regulated by its promoter methylation which may contribute to the precise treatment of AML patients.In patients with CML,the gene expression of SCIN is negatively correlated with the transcription of BCR-ABL,which may be related to the pathogenesis of CML.