PKC‐β/Alox5 axis activation promotes Bcr‐Abl‐independent TKI‐resistance in chronic myeloid leukemia

Abstract 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.