Abstract
There is growing evidence supporting a role for tumor suppressor as targets in aberrant mechanisms of DNA hypermethylation. Methylation in the promoter of tumor suppressor always plays important roles in pediatric Acute Myeloid Leukemia (AML). CDH13 gene is a tumor suppressor involved in tumorigenesis, metastasis and apoptosis in a variety of tumors. In this study, we are trying to investigate whether CDH13 was down regulated by promoter methylation in pediatric AML. MRNA transcriptional expression levels of CDH13 were evaluated by semi-quantitative PCR and real-time PCR. Methylation status of CDH13 prompter was investigated by Methylation Specific PCR (MSP) and Bisulfate Genomic Sequencing (BGS). CDH13 mRNA transcription was inactivated in AML cell lines. Promoter of CDH13 was aberrantly methylated in 55.6% (5/9) leukemia cell lines. Promoter aberrant methylation of CDH13 was detected in 34.2% (24/70) of the cases of pediatric AML. The methylation of CDH13 promoter could be detected in all FAB subtypes. There were no significant differences in clinical features between patients with and without CDH13 methylation. Expression of CDH13 was significantly lower in AML patients group compared to normal bone marrow (NBM) control samples .The expression of CDH13 in thirty controls was significantly higher than pediatric AML patients. Both patients with CDH13 methylation (n=24) and those without CDH13 methylation (n=46) had significantly lower CDH13 transcript than controls (p<0.001). CDH13 transcript was significantly lower in patients with methylated CDH13 than those without methylated CDH13 (p=0.036). Inactivation of CDH13 by promoter hypermethylation is frequent event in pediatric AML. Our results suggest that hypermethylation of CDH13 promoter might be one of early events in the development of pediatric AML.
Highlights
Acute leukemia is the most common malignancy diagnosed in children, representing nearly one third of all pediatric cancers
We have provided the first evidence of CDH13 methylation in both Acute Myeloid Leukemia (AML) cell lines and pediatric samples
Methylation Specific PCR (MSP) analysis of the methylation status of CDH13 shows aberrant methylation in pediatric AML samples compared to normal bone marrow (NBM)/Idiopathic Thrombocytopenic Purpura (ITP) control samples
Summary
Acute leukemia is the most common malignancy diagnosed in children, representing nearly one third of all pediatric cancers. Epigenetic and methylation disorders, such as aberrant promoter hypermethylation and abnormal histone modifications have been implicated in the pathogenesis of leukemia [2,3] These include aberrations in methylation, which is a key epigenetic event responsible for enhanced proliferation and self-renewal, differentiation arrest, and impaired apoptosis of leukemic cells [4]. Compared to the incidences of DNA mutations and deletions, the frequency of aberrant DNA methylation of tumor suppressor genes is high in AML. This suggests that aberrant DNA methylation has important roles in this rare cancer. These suggest that CDH13 may function as a tumor suppressor in pediatric AML
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