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Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks
Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Inserm, Angers, France; Service des Maladies du Sang, Centre Hospitalier Universitaire, Angers, France.
Institute for Biomedicine and Nutrition, NOVUM, Karolinska Institutet, Stockholm, Sweden.
Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
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2011 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 20, p. 5573-5582Article in journal (Refereed) Published
Abstract [en]

Cytogenetically normal acute myeloid leukemia (CN-AML) comprise between forty and fifty percent of all adult acute myeloid leukemia (AML) cases. In this clinically diverse group molecular aberrations such as FLT3ITD, NPM1 and CEBPA mutations recently have added to the prognostic accuracy. Aberrant DNA methylation is a hallmark of cancer including AML. We investigated in total 118 CN-AML samples in a test and a validation cohort for genome-wide promoter DNA methylation with Illumina Methylation Bead arrays and compared them to normal myeloid precursors and global gene expression. IDH and NPM1 mutations were associated with different methylation patterns (p=0.0004 and 0.04, respectively). Genome-wide methylation levels were elevated in IDH mutated samples (p=0.006). We observed a negative impact of DNA methylation on transcription. Genes targeted by Polycomb group (PcG) proteins and genes associated with bivalent histone marks in stem cells showed increased aberrant methylation in AML (p<0.0001). Furthermore, high methylation levels of PcG target genes were independently associated with better progression free (OR 0.47, p=0.01) and overall survival (OR 0.36, p=0.001). In summary, genome wide methylation patterns show preferential methylation of PcG targets with prognostic impact in CN-AML.

Place, publisher, year, edition, pages
American Society of Hematology , 2011. Vol. 118, no 20, p. 5573-5582
National Category
Hematology
Identifiers
URN: urn:nbn:se:oru:diva-22580DOI: 10.1182/blood-2011-01-332353ISI: 000297265400028PubMedID: 21960591Scopus ID: 2-s2.0-81555214615OAI: oai:DiVA.org:oru-22580DiVA, id: diva2:516603
Funder
Swedish Cancer SocietySwedish Childhood Cancer FoundationSwedish Research Council
Note

Funding Agencies:

Göran Gustafssons Foundation for Research in Natural Sciences  

Sigurd och Elsa Golje Foundation  

Ligue Contre le Cancer  

La Region Pays de la Loire/Appel a Projets du Canceropole Grand-Ouest  

Available from: 2012-04-18 Created: 2012-04-18 Last updated: 2018-05-03Bibliographically approved

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Uggla, BertilTidefelt, Ulf

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