PKC-β/Alox5 axis activation promotes Bcr-Abl-independent TKI-resistance in chronic myeloid leukemia
PKC-β/Alox5 axis activation promotes Bcr-Abl-independent TKI-resistance in chronic myeloid leukemia
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PKC-β/Alox5轴激活促进慢性粒细胞白血病中Bcr-Abl-独立的TKI-耐药
DOI：
10.1002/jcp.30301
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发表时间：
2021-02-09
影响因子：
5.6
通讯作者：
Wang, Jishi
中科院分区：
文献类型：
--
作者：
Ma, Dan;Liu, Ping;Wang, Jishi
Bcr-Abl对酪氨酸激酶抑制剂（TKI）的非依赖性耐药是导致慢性粒细胞白血病（CML）复发或急性白血病转化的重要因素。然而，其机制尚不清楚。在此，我们发现，在9种常见的蛋白激酶C（PKC）中，PKC-β过表达与TKI耐药显著相关。阻断其在CD 34+细胞和CML细胞系中的表达增加了对伊马替尼的敏感性。然后，比较PKC-β沉默与未沉默的TKI耐药CML细胞系之间的84个白血病相关基因。基因本体论术语和京都基因与基因组百科全书途径分析表明，花生四烯酸5-脂氧合酶（Alox 5）及其相关途径主要参与PKC-β过表达诱导的抗性。此外，还观察到Alox 5不仅在骨髓活检中增加，而且在来自IM耐药CML患者的CD 34（+）细胞中也增加。信号通路的探索表明ERK 1/2通路介导PKC-β上调Alox 5。同时，我们还证明了Alox 5通过失活PTEN诱导CML对TKI不敏感。体内实验中，PKC-β选择性抑制剂LY 333531延长CML-PDX小鼠模型的存活时间。总之，靶向PKC-β过表达可能是克服CML TKI耐药的一种新的治疗机制。
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-beta 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-beta 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-beta 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-beta. Meanwhile, we also proved that Alox5 induces TKI-insensitivity in CML through inactivation of PTEN. In vivo experiment, PKC-beta elective inhibitor LY333531 prolonged survival time in CML-PDX mice model. In conclusion, targeted on PKC-beta overexpression might be a novel therapy mechanism to overcome TKI-resistance in CML.