Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia
Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia
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DOI：
10.1002/ijc.21584
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发表时间：
2006-04-15
影响因子：
6.4
通讯作者：
Prósper, F
中科院分区：
文献类型：
--
作者：
Agirre, X;Román-Gómez, J;Prósper, F
PARK2基因以前被认为是常染色体隐性遗传性青少年帕金森综合征(ARJP)患者的突变靶点，最近被发现是卵巢癌、乳腺癌、肺癌和肝细胞癌的候选抑癌基因，该基因定位于第三常见脆性部位(CFS)FRA6E。PARK2通过一个双向启动子连接到一个新描述的PACRG基因，该启动子的共同启动子区域含有一个明确的CpG岛。我们研究了启动子超甲基化在不同肿瘤细胞系和原发患者样本中调节PARK2和PACRG表达的作用。PARK2和PACRG共同启动子甲基化在26%的急性淋巴细胞白血病和20%的慢性粒细胞白血病(CML)淋巴细胞危象中出现，而在卵巢、乳腺、肺、神经母细胞瘤、星形细胞瘤和结肠癌中均未发现。异常甲基化导致PARK2和PACRG基因表达下调，而ALL细胞去甲基化导致启动子去甲基化，PARK2和PACRG表达上调。通过FISH，我们证明了在ALL中PARK2和PACRG表达的缺失是由于双等位基因高甲基化所致，而不是PARK2或PACRG的缺失。综上所述，我们的结果首次证明候选抑癌基因PARK2和PACRG在人类白血病中存在表观遗传调控，提示PARK2和PACRG的异常甲基化及其调控可能在该血液病的发生发展中起一定作用。(C)2005年Wiley-Liss，Inc.
The PARK2 gene, previously identified as a mutated target in patients with autosomal recessive juvenile parkinsonism (ARJP), has recently been found to be a candidate tumor suppressor gene in ovarian, breast, lung and hepatocellular carcinoma that maps to the third common fragile site (CFS) FRA6E. PARK2 is linked to a novel described PACRG gene by a bidirectional promoter containing a defined CpG island in its common promoter region. We have studied the role of promoter hypermethylation in the regulation of PARK2 and PACRG expression in different tumor cell lines and primary patient samples. Abnormal methylation of the common promoter of PARK2 and PACRG was observed in 26% of patients with acute lymphoblastic leukemia and 20% of patients with chronic myelogenous leukemia (CML) in lymphoid blast crisis, but not in ovarian, breast, lung, neuroblastoma, astrocytoma or colon cancer cells. Abnormal methylation resulted in down-regulation of PARK2 and PACRG gene expression, while demethylation of ALL cells resulted in demethylation of the promoter and upregulation of PARK2 and PACRG expression. By FISH, we demonstrated that a lack of PARK2 and PACRG expression was due to biallelic hypermethylation and not to deletion of either PARK2 or PACRG in ALL. in conclusion, our results demonstrate for the first time that the candidate tumor suppressor genes PARK2 and PACRG are epigenetically regulated in human leukemia, suggesting that abnormal methylation and regulation of PARK2 and PACRG may play a role in the pathogenesis and development of this hematological neoplasm. (c) 2005 Wiley-Liss, Inc.