Department of Hematology and Oncology, Charité Campus Benjamin Franklin, Berlin, Germany.
Leuk Res. 2010 Dec;34(12):1610-6. doi: 10.1016/j.leukres.2010.04.013. Epub 2010 May 14.
Secreted frizzled related protein 1 (SFRP1) is an extracellular antagonist of the Wnt signalling pathway that plays an important role in the pathogenesis of solid tumours and haematopoietic malignancies. SFRP1 has been observed to be transcriptionally down-regulated due to hypermethylation in acute and chronic leukaemia, but so far not in myelodysplastic syndrome (MDS). Moreover, it has been shown that the epigenetic inactivation of SFRP1 correlates with an overexpression of the Wnt receptor Frizzled 3 (Fzd3) in acute leukaemia. Using real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) we examined mRNA expression of SFRP1 and Fzd3 in bone marrow cells derived from 121 patients with different risk types of MDS, acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). We employed pyrosequencing to quantify promoter DNA methylation in MDS and acute leukaemia. We detected significant lower mRNA transcription of SFRP1 in MDS compared to healthy individuals. However, DNA sequence mutations or frequent elevated DNA methylation levels of the SFRP1 promoter could not be observed in MDS but in AML and ALL as previously reported. The expression levels of Fzd3 were up-regulated in both acute leukaemia and MDS. Our data show a significant transcriptional down-regulation of SFRP1 as a common event in AML, ALL and - as demonstrated for the first time - in MDS. An inactivation of SFRP1 and the transcriptional up-regulation of Fzd3 seem to be associated with an activation of the Wnt signalling pathway in these haematopoietic diseases.
分泌型卷曲相关蛋白 1（SFRP1）是 Wnt 信号通路的细胞外拮抗剂，在实体瘤和造血恶性肿瘤的发病机制中发挥重要作用。已经观察到 SFRP1 由于急性和慢性白血病中的高甲基化而转录下调，但到目前为止在骨髓增生异常综合征（MDS）中尚未观察到。此外，已经表明 SFRP1 的表观遗传失活与急性白血病中 Wnt 受体卷曲蛋白 3（Fzd3）的过表达相关。使用实时定量逆转录聚合酶链反应（RT-PCR），我们检查了来自 121 例不同风险类型的 MDS、急性髓系白血病（AML）和急性淋巴细胞白血病（ALL）患者的骨髓细胞中 SFRP1 和 Fzd3 的 mRNA 表达。我们采用焦磷酸测序来定量 MDS 和急性白血病中的启动子 DNA 甲基化。与健康个体相比，我们在 MDS 中检测到 SFRP1 的 mRNA 转录显著降低。然而，如先前报道的那样，在 MDS 中未观察到 SFRP1 启动子的 DNA 序列突变或频繁升高的 DNA 甲基化水平，但在 AML 和 ALL 中观察到。Fzd3 的表达水平在急性白血病和 MDS 中均上调。我们的数据显示 SFRP1 的转录下调是 AML、ALL 中的一个常见事件，并且 - 这是首次证明 - 在 MDS 中也是如此。SFRP1 的失活和 Fzd3 的转录上调似乎与这些血液系统疾病中 Wnt 信号通路的激活相关。
