髓系白血病
癌症研究
伊马替尼
医学
下调和上调
酪氨酸激酶
蛋白激酶C
生物
信号转导
免疫学
细胞生物学
基因
遗传学
作者
Dan Ma,Ping Liu,Ping Wang,Zhen Zhou,Qin Fang,Jishi Wang
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-β 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-β 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-β 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-β. Meanwhile, we also proved that Alox5 induces TKI-insensitivity in CML through inactivation of PTEN. In vivo experiment, PKC-β elective inhibitor LY333531 prolonged survival time in CML-PDX mice model. In conclusion, targeted on PKC-β overexpression might be a novel therapy mechanism to overcome TKI-resistance in CML.
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