RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype.
RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype.
复制标题
Runx3启动子高甲基化在白血病细胞系中经常进行，并且与急性髓样白血病INV（16）亚型有关。
DOI：
10.1111/bjh.13299
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发表时间：
2015-05
影响因子：
6.5
通讯作者：
Garcia-Manero G
中科院分区：
文献类型：
--
作者：
Estécio MR;Maddipoti S;Bueso-Ramos C;DiNardo CD;Yang H;Wei Y;Kondo K;Fang Z;Stevenson W;Chang KS;Pierce SA;Bohannan Z;Borthakur G;Kantarjian H;Garcia-Manero G
相关和功能研究支持RUNX基因家族参与血液系统恶性肿瘤。为了阐明表观遗传学在RUNX失活中的作用，我们评估了23个白血病细胞系和来自急性髓性白血病（AML）、急性淋巴细胞白血病（ALL）和骨髓增生异常综合征（MDS）患者的样本中RUNX 1、2和3的启动子DNA甲基化。RUNX1和RUNX2基因启动子在细胞系和临床样本中大多未甲基化。RUNX3的高甲基化在细胞系中很常见（74%），并且在患者样本中具有高度变异性，与细胞遗传学状态有明确的相关性。与其他AML亚型（其他49例病例中的31%）相比，在inv（16）（p13.1q22）AML患者中发现了高频率的RUNX3超甲基化（20例研究病例中的85%）。RUNX3甲基化在ALL中也很常见（6例中为100%），但在MDS中较低（21%）。为了支持功能性作用，RUNX3的高甲基化与低水平的蛋白质相关，并且用DNA去甲基化剂地西他滨处理细胞系导致mRNA重新表达。此外，无RUNX3甲基化的非inv（16）（p13.1q22）AML患者的无复发生存率显著优于甲基化病例（p=0.016）。这些结果表明RUNX3沉默是inv（16）（p13.1q22）白血病中的重要事件。
Correlative and functional studies support the involvement of the RUNX gene family in hematological malignancies. To elucidate the role of epigenetics in RUNX inactivation, we evaluated promoter DNA methylation of RUNX1, 2, and 3 in 23 leukemia cell lines and samples from acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplatic syndromes (MDS) patients. RUNX1 and RUNX2 gene promoters were mostly unmethylated in cell lines and clinical samples. Hypermethylation of RUNX3 was frequent among cell lines (74%) and highly variable among patient samples, with clear association to cytogenetic status. High frequency of RUNX3 hypermethylation (85% of the 20 studied cases) was found in AML patients with inv(16)(p13.1q22) compared to other AML subtypes (31% of the other 49 cases). RUNX3 hypermethylation was also frequent in ALL (100% of the 6 cases) but low in MDS (21%). In support of a functional role, hypermethylation of RUNX3 was correlated with low levels of protein, and treatment of cell lines with the DNA demethylating agent decitabine resulted in mRNA re-expression. Furthermore, relapse-free survival of non-inv(16)(p13.1q22) AML patients without RUNX3 methylation was significantly better (p=0.016) than that of methylated cases. These results suggest that RUNX3 silencing is an important event in inv(16)(p13.1q22) leukemias.