Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks

被引：70

作者：

Deneberg, Stefan ^{[1
]}

Guardiola, Philippe ^{[2
,3
]}

Lennartsson, Andreas ^{[4
]}

Qu, Ying ^{[1
]}

Gaidzik, Verena ^{[5
]}

Blanchet, Odile ^{[2
,6
]}

Karimi, Mohsen ^{[1
]}

Bengtzen, Sofia ^{[1
]}

Nahi, Hareth ^{[1
]}

Uggla, Bertil ^{[7
]}

Tidefelt, Ulf ^{[7
]}

Hoglund, Martin ^{[8
]}

Paul, Christer ^{[1
]}

Ekwall, Karl ^{[4
]}

Doehner, Konstanze ^{[5
]}

Lehmann, Soren ^{[1
]}

机构：

[1] Karolinska Univ, Huddinge Hosp, Karolinska Inst, Dept Internal Med Hematol, S-14186 Huddinge, Sweden

[2] INSERM, U892, Angers, France

[3] Ctr Hosp Univ, Serv Malad Sang, Angers, France

[4] Karolinska Inst, NOVUM, Inst Biomed & Nutr, Stockholm, Sweden

[5] Univ Hosp, Dept Internal Med 3, Ulm, Germany

[6] Ctr Hosp Univ, Hematol Lab, Angers, France

[7] Orebro Univ Hosp, Dept Hematol, Orebro, Sweden

[8] Univ Uppsala Hosp, Dept Hematol, Uppsala, Sweden

来源：

BLOOD | 2011年 / 118卷 / 20期

基金：

瑞典研究理事会;

关键词：

EPIGENETIC CHANGES; MICROARRAY DATA; IDH2; MUTATIONS; CANCER-CELLS; GENES; POLYCOMB; HYPERMETHYLATION; DIFFERENTIATION; EPIGENOMICS; SIGNATURE;

D O I：

10.1182/blood-2011-01-332353

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Cytogenetically normal acute myeloid leukemia (CN-AML) compose between 40% and 50% of all adult acute myeloid leukemia (AML) cases. In this clinically diverse group, molecular aberrations, such as FLT3-ITD, 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 with normal myeloid precursors and global gene expression. IDH and NPM1 mutations were associated with different methylation patterns (P = .0004 and .04, respectively). Genome-wide methylation levels were elevated in IDH-mutated samples (P = .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 < .0001). Furthermore, high methylation levels of PcG target genes were independently associated with better progression-free survival (odds ratio = 0.47, P = .01) and overall survival (odds ratio = 0.36, P = .001). In summary, genome-wide methylation patterns show preferential methylation of PcG targets with prognostic impact in CN-AML. (Blood. 2011;118(20):5573-5582)

引用

页码：5573 / 5582

页数：10

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