AKAP12, a gene with tumour suppressor properties, is a target of promoter DNA methylation in childhood myeloid malignancies
AKAP12, a gene with tumour suppressor properties, is a target of promoter DNA methylation in childhood myeloid malignancies
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DOI：
10.1111/j.1365-2141.2007.06709.x
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发表时间：
2007-09-01
影响因子：
6.5
通讯作者：
Niemeyer, Charlotte M.
中科院分区：
文献类型：
--
作者：
Flotho, Christian;Paulun, Annika;Niemeyer, Charlotte M.
A-激酶锚定蛋白 12 (AKAP12) 是一种支架蛋白，参与有丝分裂调节和其他信号传导过程，并可能发挥肿瘤抑制功能。我们假设 AKAP12 基因的表观遗传抑制可能发生在恶性骨髓疾病中。这项研究表明，AKAP12 的 5' CpG 岛在正常造血祖细胞和粒细胞中未甲基化，但在 Kasumi-1 和 SKNO-1 白血病成髓细胞中表现出深度甲基化。相应地，AKAP12 在正常祖细胞中表达，但在白血病细胞中转录沉默。通过单独使用 MS275 或与 zebularine 联合处理，Kasumi-1 和 SKNO-1 细胞中的 AKAP12 重新表达，表明基因抑制的表观遗传机制。在一组 21 份来自患有恶性骨髓疾病（包括难治性血细胞减少症、RAEB、幼年粒单核细胞白血病和 AML）的儿童的血液或骨髓样本中，在一例难治性原始细胞过多贫血 (RAEB) 病例和两例急性髓系白血病 (AML) 病例中发现了 AKAP12 高甲基化。虽然 AKAP12 功能之前并未与白血病发生相关，但我们的结果提出了 AKAP12 表观遗传沉默与骨髓恶性肿瘤有关的可能性。
A-kinase anchor protein 12 (AKAP12) is a scaffold protein that participates in mitotic regulation and other signalling processes and probably exerts tumour suppressor function. We hypothesized that epigenetic repression of the AKAP12 gene might occur in malignant myeloid disorders. This study demonstrated that the 5' CpG island of AKAP12 was unmethylated in normal haematopoietic progenitors and granulocytes but exhibited profound methylation in Kasumi-1 and SKNO-1 leukaemic myeloblasts. Correspondingly, AKAP12 was expressed in normal progenitors but transcriptionally silent in leukaemic blasts. Re-expression of AKAP12 in Kasumi-1 and SKNO-1 cells was accomplished by treatment with MS275 alone or in combination with zebularine, indicating epigenetic mechanisms of gene repression. AKAP12 hypermethylation was found in one case of refractory anaemia with excess blasts (RAEB) and two cases of acute myeloid leukaemia (AML) in a panel of 21 blood or bone marrow samples from children with malignant myeloid disorders including refractory cytopenia, RAEB, juvenile myelomonocytic leukaemia and AML. While AKAP12 function has not been previously linked to leukaemogenesis, our results raise the possibility that epigenetic silencing of AKAP12 is involved in myeloid malignancies.