The Bone Marrow-Mediated Protection of Myeloproliferative Neoplastic Cells to Vorinostat and Ruxolitinib Relies on the Activation of JNK and PI3K Signalling Pathways.
The Bone Marrow-Mediated Protection of Myeloproliferative Neoplastic Cells to Vorinostat and Ruxolitinib Relies on the Activation of JNK and PI3K Signalling Pathways.
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DOI：
10.1371/journal.pone.0143897
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Almeida AM
中科院分区：
文献类型：
--
作者：
Cardoso BA;Belo H;Barata JT;Almeida AM
经典的bcr - abl阴性骨髓增生性肿瘤（MPN）是一组异质性血液病，其特征是组成性JAK-STAT通路激活。Ruxolitinib（一种jak1 /2特异性抑制剂）的靶向治疗可以改善症状，但不能消除肿瘤克隆。组蛋白去乙酰化酶抑制剂（HDACi）也有类似的效果，尽管耐受性较差。在这里，我们发现骨髓（BM）基质细胞（HS-5）保护MPN来源的细胞系（SET-2； HEL和uke1）和MPN患者来源的BM细胞免受Ruxolitinib和HDACi Vorinostat的细胞毒性作用。这种保护作用至少部分是由骨髓基质中可溶性因子的分泌介导的。此外，它还与细胞稳态重要信号通路的激活相关，如JAK-STAT、PI3K、JNK、MEK-ERK和NF-κB。重要的是，JNK和PI3K途径的药理抑制完全取消了BM对MPN细胞系和MPN患者样本的保护作用。我们的研究结果揭示了肿瘤存活的机制，并可能为治疗MPN提供新的治疗方法。
The classical BCR-ABL-negative Myeloproliferative Neoplasms (MPN) are a group of heterogeneous haematological diseases characterized by constitutive JAK-STAT pathway activation. Targeted therapy with Ruxolitinib, a JAK1/2-specific inhibitor, achieves symptomatic improvement but does not eliminate the neoplastic clone. Similar effects are seen with histone deacetylase inhibitors (HDACi), albeit with poorer tolerance. Here, we show that bone marrow (BM) stromal cells (HS-5) protected MPN-derived cell lines (SET-2; HEL and UKE-1) and MPN patient-derived BM cells from the cytotoxic effects of Ruxolitinib and the HDACi Vorinostat. This protective effect was mediated, at least in part, by the secretion of soluble factors from the BM stroma. In addition, it correlated with the activation of signalling pathways important for cellular homeostasis, such as JAK-STAT, PI3K, JNK, MEK-ERK and NF-κB. Importantly, the pharmacological inhibition of JNK and PI3K pathways completely abrogated the BM protective effect on MPN cell lines and MPN patient samples. Our findings shed light on mechanisms of tumour survival and may indicate novel therapeutic approaches for the treatment of MPN.