CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors.
CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors.
复制标题
作者：
DNA低甲基化药物地西他滨维持正常的造血干细胞（HSC）自我更新，但诱导急性髓性白血病（AML）细胞的终末分化。这些对比细胞命运的基础，以及地西他滨选择性CpG低甲基化的基础，知之甚少。启动子CpG，与甲基化测定的微阵列，分类的甲基化变化的方向与正常的骨髓成熟。在AML细胞中，成熟应答性CpG的甲基化模式表明至少部分成熟。与部分成熟一致，在基因表达分析中，AML细胞表达高水平的关键谱系特异性因子CEBPA，但相对低水平的关键晚期分化驱动因子CEBPE。在质谱甲基化分析中，在粒细胞成熟过程中通常低甲基化的CEBPE启动子CpG在AML细胞中显著高甲基化。地西他滨处理诱导AML细胞的细胞分化，并且最大的甲基化降低在随着髓样成熟而低甲基化的CpG处，包括CEBPE启动子CpG。相比之下，地西他滨处理的正常HSC保留了未成熟的形态，并且在未成熟细胞中甲基化较少的CpG处甲基化显著降低。谱系特异性因子的高表达和一些关键晚期分化基因的异常表观遗传抑制将AML细胞与正常HSC区分开来，并可以解释地西他滨的分化和甲基化反应的差异。
The DNA hypomethylating drug decitabine maintains normal hematopoietic stem cell (HSC) self-renewal but induces terminal differentiation in acute myeloid leukemia (AML) cells. The basis for these contrasting cell-fates, and for selective CpG hypomethylation by decitabine, is poorly understood. Promoter CpGs, with methylation measured by microarray, were classified by the direction of methylation change with normal myeloid maturation. In AML cells, the methylation pattern at maturation-responsive CpG suggested at least partial maturation. Consistent with partial maturation, in gene expression analyses, AML cells expressed high levels of the key lineage-specifying factor CEBPA, but relatively low levels of the key late-differentiation driver CEBPE. In methylation analysis by mass-spectrometry, CEBPE promoter CpG that are usually hypomethylated during granulocyte maturation were significantly hypermethylated in AML cells. Decitabine treatment induced cellular differentiation of AML cells, and the largest methylation decreases were at CpG that are hypomethylated with myeloid maturation, including CEBPE promoter CpG. In contrast, decitabine-treated normal HSC retained immature morphology, and methylation significantly decreased at CpG that are less methylated in immature cells. High expression of lineage-specifying factor and aberrant epigenetic repression of some key late-differentiation genes distinguishes AML cells from normal HSC and could explain the contrasting differentiation and methylation responses to decitabine.
登录
查看更多内容
影响因子：
50.3
作者：
Kirstetter, Peggy;Schuster, Mikkel B.;Nerlov, Claus
通讯作者：
Nerlov, Claus
影响因子：
14.9
作者：
Heinemeyer, T;Wingender, E;Kolchanov, NA
通讯作者：
Kolchanov, NA
影响因子：
20.3
作者：
Blair, A;Hogge, DE;Sutherland, HJ
通讯作者：
Sutherland, HJ
影响因子：
20.3
作者：
Chung, Yun Shin;Kim, Hye Joung;Oh, Il-Hoan
通讯作者：
Oh, Il-Hoan
影响因子：
30.8
作者：
Broeske, Ann-Marie;Vockentanz, Lena;Rosenbauer, Frank
通讯作者：
Rosenbauer, Frank