Early B-cell factor 3 EBF3 is a novel tumor suppressor gene with promoter hypermethylation in pediatric acute myeloid leukemiaReportar como inadecuado




Early B-cell factor 3 EBF3 is a novel tumor suppressor gene with promoter hypermethylation in pediatric acute myeloid leukemia - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal of Experimental and Clinical Cancer Research

, 34:4

First Online: 22 January 2015Received: 15 September 2014Accepted: 27 November 2014DOI: 10.1186-s13046-014-0118-1

Cite this article as: Tao, YF., Xu, LX., Lu, J. et al. J Exp Clin Cancer Res 2015 34: 4. doi:10.1186-s13046-014-0118-1

Abstract

BackgroundPediatric acute myeloid leukemia AML comprises up to 20% of all childhood leukemia. Recent research shows that aberrant DNA methylation patterning may play a role in leukemogenesis. The epigenetic silencing of the EBF3 locus is very frequent in glioblastoma. However, the expression profiles and molecular function of EBF3 in pediatric AML is still unclear.

MethodsTwelve human acute leukemia cell lines, 105 pediatric AML samples and 30 normal bone marrow-idiopathic thrombocytopenic purpura NBM-ITP control samples were analyzed. Transcriptional level of EBF3 was evaluated by semi-quantitative and real-time PCR. EBF3 methylation status was determined by methylation specific PCR MSP and bisulfite genomic sequencing BGS. The molecular mechanism of EBF3 was investigated by apoptosis assays and PCR array analysis.

ResultsEBF3 promoter was hypermethylated in 10-12 leukemia cell lines. Aberrant EBF3 methylation was observed in 42.9% 45-105 of the pediatric AML samples using MSP analysis, and the BGS results confirmed promoter methylation. EBF3 expression was decreased in the AML samples compared with control. Methylated samples revealed similar survival outcomes by Kaplan-Meier survival analysis. EBF3 overexpression significantly inhibited cell proliferation and increased apoptosis. Real-time PCR array analysis revealed 93 dysregulated genes possibly implicated in the apoptosis of EBF3-induced AML cells.

ConclusionIn this study, we firstly identified epigenetic inactivation of EBF3 in both AML cell lines and pediatric AML samples for the first time. Our findings also showed for the first time that transcriptional overexpression of EBF3 could inhibit proliferation and induce apoptosis in AML cells. We identified 93 dysregulated apoptosis-related genes in EBF3-overexpressing, including DCC, AIFM2 and DAPK1. Most of these genes have never been related with EBF3 over expression. These results may provide new insights into the molecular mechanism of EBF3-induced apoptosis; however, further research will be required to determine the underlying details.

Our findings suggest that EBF3 may act as a putative tumor suppressor gene in pediatric AML.

KeywordsEarly B-cell factor 3 Pediatric acute myeloid leukemia Methylation Tumor suppressor Real-time PCR array AbbreviationsALLAcute lymphoblastic leukemia

AMLAcute myeloid leukemia

MSPMethylation specific PCR

BGSBisulfite genomic sequencing

NBMNormal bone marrow

ITPIdiopathic thrombocytopenic purpura

Yan-Fang Tao, Li-Xiao Xu, and Jun Lu, these authors contributed equally to this work.

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Autor: Yan-Fang Tao - Li-Xiao Xu - Jun Lu - Shao-Yan Hu - Fang Fang - Lan Cao - Pei-Fang Xiao - Xiao-Juan Du - Li-Chao Sun - Zhi

Fuente: https://link.springer.com/



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