Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Blood. 2011 Nov 17;118(20):5573-82. doi: 10.1182/blood-2011-01-332353. Epub 2011 Sep 29.
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.
核型正常的急性髓细胞白血病（CN-AML）占所有成人急性髓细胞白血病（AML）病例的 40%至 50%。在这个临床多样化的群体中，分子异常，如 FLT3-ITD、NPM1 和 CEBPA 突变，最近增加了预后准确性。异常的 DNA 甲基化是癌症的标志，包括 AML。我们使用 Illumina Methylation Bead 阵列在一个测试和验证队列中总共研究了 118 个 CN-AML 样本的全基因组启动子 DNA 甲基化，并将其与正常髓样前体和全局基因表达进行了比较。IDH 和 NPM1 突变与不同的甲基化模式相关（P =.0004 和.04，分别）。IDH 突变样本中全基因组甲基化水平升高（P =.006）。我们观察到 DNA 甲基化对转录有负面影响。多梳组（PcG）蛋白靶向的基因和与干细胞中双价组蛋白标记相关的基因在 AML 中表现出异常甲基化增加（P <.0001）。此外，PcG 靶基因的高甲基化水平与无进展生存期（优势比=0.47，P =.01）和总生存期（优势比=0.36，P =.001）的独立改善相关。总之，全基因组甲基化模式显示了 CN-AML 中具有预后影响的 PcG 靶基因的优先甲基化。
