Epigenetic dysregulation of the Wnt signalling pathway in chronic lymphocytic leukaemia
Epigenetic dysregulation of the Wnt signalling pathway in chronic lymphocytic leukaemia
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DOI：
10.1136/jcp.2008.060152
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发表时间：
2008-11-01
影响因子：
3.4
通讯作者：
Liang, R.
中科院分区：
文献类型：
--
作者：
Chim, C. S.;Pang, R.;Liang, R.
背景：近年来，WNT信号与肿瘤的发病机制有关。方法：本研究采用甲基化特异性聚合酶链式反应技术，检测了慢性淋巴细胞白血病(CLL)患者外周血中WNT信号的活性，以及7种可溶性WNT拮抗剂基因WIF1、DKK3、APC、SFRP1、SFRP2、sFRP4和SFRP5的甲基化状态。在诊断的CLL骨髓样本中，高达36.4%的样本检测到这七个基因的甲基化。此外，23例(52.3%)患者存在7个基因中至少一个基因的甲基化，其中14例(60.8%)存在两个或更多Wnt抑制基因的甲基化。除高龄与DKK3甲基化有关外，基因高甲基化与临床特征(包括年龄、性别、确诊时淋巴细胞计数、RAI分期和低危核型)或生存无关。结论：CLL B淋巴细胞中WNT信号被结构性激活，与多种可溶性WNT拮抗剂基因甲基化有关。在初级CLL骨髓标本中，这些可溶性Wnt拮抗剂基因的甲基化，有时是多个基因，提示在CLL的发病机制中起着重要作用。此外，这项研究强调了研究调控细胞途径的一组基因而不是单个基因甲基化的重要性。
Background: Wnt signalling has recently been implicated in the pathogenesis of cancer.Methods: This study investigated the activity of Wnt signalling in peripheral blood chronic lymphocytic leukaemia (CLL) lymphocytes, and the methylation status of seven soluble Wnt antagonist genes, including WIF1, DKK3, APC, SFRP1, SFRP2, SFRP4 and SFRP5, by using methylation-specific PCR in the peripheral blood CLL lymphocytes and bone marrow samples of patients with CLL at diagnosis.Results: In the peripheral blood CLL lymphocytes, constitutive activation of Wnt signalling was detected, associated with hypermethylation of the soluble Wnt inhibitor genes. In the diagnostic CLL marrow samples, methylation of the seven genes was detected in up to 36.4% of samples. Moreover, 23 (52.3%) patients had methylation of at least one of the seven genes, of whom 14 (60.8%) had methylation of two or more Wnt inhibitor genes. Apart from an association of advanced age with DKK3 methylation, there was no association of gene hypermethylation with either clinical characteristics (including age, gender, lymphocyte count at diagnosis, Rai stage and poor-risk karyotype) or survival.Conclusion: Wnt signalling is constitutively activated in CLL B lymphocytes in association with methylation of multiple soluble Wnt antagonist genes. Methylation of these soluble Wnt antagonist genes, occasionally multiple genes, in primary CLL marrow samples suggests an important role in CLL pathogenesis. Moreover, this study underscored the importance of studying methylation of a panel of, but not individual, genes regulating a cellular pathway.