A crosstalk between the Wnt and the adhesion-dependent signaling pathways governs the chemosensitivity of acute myeloid leukemia
A crosstalk between the Wnt and the adhesion-dependent signaling pathways governs the chemosensitivity of acute myeloid leukemia
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DOI：
10.1038/sj.onc.1209346
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发表时间：
2006-05-25
期刊：
影响因子：
8
通讯作者：
Ysebaert, L.
中科院分区：
文献类型：
--
作者：
De Toni, F.;Racaud-Sultan, C.;Ysebaert, L.
化疗后复发是急性髓细胞白血病（AML）患者生存的主要障碍。为了研究造血生态位在白血病细胞化疗耐药性中的作用，我们研究了两种途径：一种是由粘附分子/整合素介导的，另一种是由形态原Wnt途径的可溶性因子介导的。在我们的研究中，白血病母细胞与纤连蛋白的粘附和加入Wnt拮抗剂在细胞存活测定中独立地诱导AML细胞对柔红霉素的抗性。使用药理学抑制剂和siRNA，我们发现两种抗性途径都需要糖原合成酶激酶3 β（GSK 3 β）的活性。此外，GSK 3 β下游的AML细胞保护由NF-κ B介导。发现粘附和Wnt途径之间的联系，因为U937在人成骨细胞（造血生态位的组分）上的粘附触发Wnt拮抗剂sFRP-1的分泌并支持对柔红霉素的抗性。成骨细胞条件培养基也可以赋予化疗耐药的U937细胞悬浮培养，这种细胞保护作用被废除后耗尽sFRP-1。在这种潜在的双重体内抗性的背景下，共同信号GSK 3 β及其靶NF-κ B的调节剂可以代表重要的新型治疗工具。
Relapses following chemotherapy are a major hindrance to patients' survival in acute myeloid leukemia (AML). To investigate the role of the hematopoietic niche in the chemoresistance of leukemic cells, we examined two pathways: one mediated by adhesion molecules/integrins, and the other by soluble factors of the morphogen Wnt pathway. In our study, both the adhesion of leukemic blasts to fibronectin and the addition of Wnt antagonists induced, independently, resistance of AML cells to daunorubicin in a cell survival assay. Using pharmacological inhibitors and siRNA, we showed that both resistance pathways required the activity of the glycogen synthase kinase 3 beta (GSK3 beta). Moreover, the AML cell protection downstream of GSK3 beta was mediated by NF-kappa B. A link between the adhesion and the Wnt pathway was found, as adhesion of U937 on human osteoblasts, a component of the hematopoietic niche, triggered the secretion of the Wnt antagonist sFRP-1 and supported resistance to daunorubicin. The osteoblast-conditioned medium could also confer chemoresistance to U937 cells cultured in suspension, and this cell protective effect was abrogated after depletion of sFRP-1. In the context of this potential double in vivo resistance, modulators of the common signal GSK3 beta and of its target NF-kappa B could represent important novel therapeutic tools.