Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases.

This study was partially supported by grants from the Spanish Fondo de Investigaciones Sanitarias FIS 09/01543, Proyectos de Investigación del SACYL 355/A/09, COST Action “EuGESMA” (BM0801), Northern Ireland Leukaemia Research Fund (NILRF), Northern Ireland Assembly Department of Education and Learning, Obra Social Banca Cívica (Caja Burgos), and by the >Acción Transversal del Cáncer> project, through an agreement between the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation, the Cancer Research Foundation of Salamanca University and the Redes de Investigación RTIIC (FIS). MdR is fully upported by an >Ayuda Predoctoral” by the Fundación Española de Hematología y Hemoterapia.

Peer Reviewed