Aberrant DNA methylation and epigenetic inactivation of Eph receptor tyrosine kinases and ephrin ligands in acute lymphoblastic leukemia
Aberrant DNA methylation and epigenetic inactivation of Eph receptor tyrosine kinases and ephrin ligands in acute lymphoblastic leukemia
复制标题
DOI：
10.1182/blood-2009-05-222208
复制
发表时间：
2010-03-25
期刊：
影响因子：
20.3
通讯作者：
Garcia-Manero, Guillermo
中科院分区：
文献类型：
--
作者：
Kuang, Shao-Qing;Bai, Hao;Garcia-Manero, Guillermo
Eph受体及其肝配蛋白配体参与正常造血发育和肿瘤发生。使用甲基化 CpG 岛扩增/DNA 启动子微阵列，我们鉴定了几种 EPH 受体和 EPHRIN 基因作为急性淋巴细胞白血病 (ALL) 的潜在高甲基化靶点。我们随后通过亚硫酸氢盐焦磷酸测序研究了 Eph/ephrin 家族的 DNA 甲基化状态。在白血病细胞系和原代 ALL 骨髓样本中检测到 EPHA2、-A4、-A5、-A6、-A7、-A10、EPHB1、-B2、-B3、-B4、EFNA1、-A3、-A5 以及 EFNB1 和 -B2 基因的高甲基化。 EPHB4、EFNB2 和 EFNA5 基因的表达分析表明 DNA 甲基化与基因沉默相关。我们克隆了 EPHB4 的启动子区域，并证明启动子高甲基化可导致 EPHB4 转录沉默。通过慢病毒转导恢复 EPHB4 表达，导致 EPHB4 甲基化和沉默的 Raji 细胞增殖减少和细胞凋亡。最后，我们证明磷酸化的 Akt 在转导 EPHB4 的 Raji 细胞中下调。这些结果表明，EPH/EPHRIN 家族基因高甲基化导致的表观遗传沉默有助于 ALL 的发病机制，并且 EPHB4 可以在 ALL 中充当肿瘤抑制因子。 （血。2010；115：2412-2419）
Eph receptors and their ephrin ligands are involved in normal hematopoietic development and tumorigenesis. Using methylated CpG island amplification/DNA promoter microarray, we identified several EPH receptor and EPHRIN genes as potential hypermethylation targets in acute lymphoblastic leukemia (ALL). We subsequently studied the DNA methylation status of the Eph/ephrin family by bisulfite pyrosequencing. Hypermethylation of EPHA2, -A4, -A5, -A6, -A7, -A10, EPHB1, -B2, -B3, -B4, EFNA1, -A3, -A5, and EFNB1 and -B2 genes was detected in leukemia cell lines and primary ALL bone marrow samples. Expression analysis of EPHB4, EFNB2, and EFNA5 genes demonstrated that DNA methylation was associated with gene silencing. We cloned the promoter region of EPHB4 and demonstrated that promoter hypermethylation can result in EPHB4 transcriptional silencing. Restoration of EPHB4 expression by lentiviral transduction resulted in reduced proliferation and apoptotic cell death in Raji cells in which EPHB4 is methylated and silenced. Finally, we demonstrated that phosphorylated Akt is down-regulated in Raji cells transduced with EPHB4. These results suggest that epigenetic silencing by hypermethylation of EPH/EPHRIN family genes contributes to ALL pathogenesis and that EPHB4 can function as a tumor suppressor in ALL. (Blood. 2010;115:2412-2419)