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首页> 外文期刊>Journal of cellular physiology. >PKC-p/Alox5 axis activation promotes Bcr-Abl-independent TKI-resistance in chronic myeloid leukemia
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PKC-p/Alox5 axis activation promotes Bcr-Abl-independent TKI-resistance in chronic myeloid leukemia

机译：PKC-p / Alox5轴激活促进Bcr-Abl-independent TKI-resistance在慢性骨髓性白血病

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摘要

Bcr-Abl independent resistance to tyrosine kinase inhibitor (TKI) is a crucial factor lead to relapse or acute leukemia transformation in chronic myeloid leukemia (CML). However, its mechanism is still unclear. Herein, we found that of nine common protein kinases C (PKCs), PKC-(3 overexpression was significantly related with TKI resistance. Blockage of its expression in CD34+ cells and CML cell lines increased sensitivity to imatinib. Then, eighty-four leukemia related genes were compared between TKI-resistant CML cell lines with PKC-(3 silenced or not. Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that Arachidonate 5-lipoxygenase (Alox5) and its relative pathway mainly participated in the resistance induced by PKC-(3 overexpression. It's also observed that Alox5 was increased not only in bone marrow biopsy but also in CD34+ cells derived from IM-resistant CML patients. The signaling pathway exploration indicated that ERK1/2 pathway mediates Alox5 upregulation by PKC-(3. Meanwhile, we also proved that Alox5 induces TKI-insensitivity in CML through inactivation of PTEN. In vivo experiment, PKC-(3 elective inhibitor LY333531 prolonged survival time in CML-PDX mice model. In conclusion, targeted on PKC-(3 overexpression might be a novel therapy mechanism to overcome TKI-resistance in CML.
机译：bcr - abl独立抗酪氨酸激酶抑制剂(TKI)是导致一个至关重要的因素复发或急性白血病转型慢性粒细胞白血病(CML)。机制尚不清楚。九个常见的蛋白激酶C (PKCs), PKC - (3超表达与TKI显著相关阻力。细胞和CML细胞系敏感性增加伊马替尼。基因TKI-resistant CML之间的比较细胞系PKC -(3沉默。本体术语和京都基因和百科全书基因组途径分析表明,花生四烯酸5-lipoxygenase (Alox5)及其相对路径主要参与了电阻引起的PKC -(3超表达。Alox5增加不仅在骨髓CD34 +细胞来源于活检也IM-resistant CML患者。勘探表明ERK1/2通路介导Alox5 upregulation PKC -(3。我们也证明Alox5诱发TKI-insensitivity CML通过失活PTEN。抑制剂LY333531延长生存时间CML-PDX小鼠模型。PKC -(3超表达可能是一个新颖的治疗机制来克服TKI-resistance CML。

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