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Myelodysplasias

Genome-wide profiling of methylation identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes

Leukemia volume 27, pages 610–618 (2013)Cite this article

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Abstract

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.

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Acknowledgements

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 Leukemia 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 supported by an "Ayuda Predoctoral’ by the Fundación Española de Hematología y Hemoterapia. We thank Irene Rodríguez, Sara González, Teresa Prieto, Ma Ángeles Ramos, Almudena Martín, Ana Díaz, Ana Simón, María del Pozo and Vanesa Gutiérrez of the Centro de Investigación del Cáncer, Salamanca, Spain and Anne Carson from the Centre for Cancer Research and Cell Biology, Belfast, UK, for their technical assistance.

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  1. K I Mills and J M Hernández-Rivas: These authors contributed equally to this work.

Authors and Affiliations

  1. IBMCC, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Salamanca, Spain

    M del Rey, S Aibar, J De Las Rivas & J M Hernández-Rivas

  2. IBSAL, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain

    M del Rey, S Aibar, M E Alonso, M Díez-Campelo, N C Gutiérrez, J L García, J De Las Rivas & J M Hernández-Rivas

  3. Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK

    K O'Hagan, M Dellett, H A A Colyer, R N Armstrong, D J Sharpe & K I Mills

  4. Servicio de Hematología y Departamento de Medicina, Hospital Universitario de Salamanca, Salamanca, Spain

    M E Alonso, M Díez-Campelo, N C Gutiérrez & J M Hernández-Rivas

  5. Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL)-HUSAL, Castilla y León, Spain

    J L García

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del Rey, M., O'Hagan, K., Dellett, M. et al. Genome-wide profiling of methylation identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes. Leukemia 27, 610–618 (2013). https://doi.org/10.1038/leu.2012.253

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