CBFB-MYH11 hypomethylation signature and PBX3 differential methylation revealed by targeted bisulfite sequencing in patients with acute myeloid leukemia

Journal of Hematology & Oncology

Vladimír Bene¿²  Petr Cetkovský³  Kyra Michalová¹  Ota Fuchs⁴  Martin Vostrý⁴  Arno¿t Koste?ka⁴  Michaela Dostálová Merkerová⁴  Zden?k Krej?ík⁴  Jana Marková³  Cyril ¿álek³  Ji?í Schwarz³  Cedrik Ha¿kovec⁴  Markus Hsi-Yang Fritz²  Hana Hájková⁴ 

[1] Center of Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University in Prague, U Nemocnice 2, Prague, Czech Republic;European Molecular Biology Laboratory (EMBL), Core Facilities and Services, Meyerhofstraße 1, Heidelberg, Germany;Clinical Department, Institute of Hematology and Blood Transfusion, U Nemocnice 1, Prague, Czech Republic;Department of Molecular Genetics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, Prague, Czech Republic

关键词: PBX3;    Targeted bisulfite sequencing;    DNA methylation;    CBFB-MYH11;    Acute myeloid leukemia;   

Others  :  1144296
DOI  :  10.1186/s13045-014-0066-4

 received in 2014-03-25, accepted in 2014-09-06,  发布年份 2014

【 摘 要 】

Background

Studying DNA methylation changes in the context of structural rearrangements and point mutations as well as gene expression changes enables the identification of genes that are important for disease onset and progression in different subtypes of acute myeloid leukemia (AML) patients. The aim of this study was to identify differentially methylated genes with potential impact on AML pathogenesis based on the correlation of methylation and expression data.

Methods

The primary method of studying DNA methylation changes was targeted bisulfite sequencing capturing approximately 84 megabases (Mb) of the genome in 14 diagnostic AML patients and a healthy donors¿ CD34+ pool. Subsequently, selected DNA methylation changes were confirmed by 454 bisulfite pyrosequencing in a larger cohort of samples. Furthermore, we addressed gene expression by microarray profiling and correlated methylation of regions adjacent to transcription start sites with expression of corresponding genes.

Results

Here, we report a novel hypomethylation pattern, specific to CBFB-MYH11 fusion resulting from inv(16) rearrangement that is associated with genes previously described as upregulated in inv(16) AML. We assume that this hypomethylation and corresponding overexpresion occurs in the genes whose function is important in inv(16) leukemogenesis. Further, by comparing all targeted methylation and microarray expression data, PBX3 differential methylation was found to correlate with its gene expression. PBX3 has been recently shown to be a key interaction partner of HOX genes during leukemogenesis and we revealed higher incidence of relapses in PBX3-overexpressing patients.

Conclusions

We discovered new genomic regions with aberrant DNA methylation that are associated with expression of genes involved in leukemogenesis. Our results demonstrate the potential of the targeted approach for DNA methylation studies to reveal new regulatory regions.

【 授权许可】

   
2014 Hajkova et al.; licensee BioMed Central Ltd.

【 图 表 】

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