Akademik Veri Yönetim Sistemi
HEMATOLOGY, cilt.23, sa.10, ss.765-770, 2018 (SCI-Expanded)
Objective: Chronic myleoid leukemia (CML) is a myeloproliferative disorder characterized with the constitutive activation of Bcr-Abl tyrosine kinase which is a target for imatinib, the first line treatment option for CML. Constitutive activation of NF kappa B and beta-catenin signaling promotes cellular proliferation and survival and resistance to Imatinib therapy in CML. Akirin-2 is a nuclear protein which is required for NF kappa B dependent gene expression as a cofactor and has been linked to Wnt/beta-catenin pathway. The purpose of this study is to examine Akirin-2, NF kappa B and beta-catenin in imatinib resistance of CML and to test if any direct physical protein-protein interaction exists between NFkB and both beta-catenin and Akirin-2. Methods: RT-PCR and western blot were performed to determine Akirin-2, NF kappa B-p65 and beta-catenin gene and protein expressions, Co-immunoprecipitation and chromatin immunoprecipitation analysis were carried out to detect the direct physical interactions and binding of NF kappa B-p65 and beta-catenin proteins to MDR1 promoter region, respectively. Results: beta-catenin and NF kappa B-p65 proteins bound to DNA promoter regions of MDR1 in imatinib-sensitive and resistant CML cells, whereas any direct protein-protein interaction could not be found between NF kappa B-p65 and Akirin-2 or beta-catenin proteins. Nuclear beta-catenin and NF kappa B-p65 levels increased in imatinib resistance. Moreover, increased Akirin-2 protein accumulation in the nucleus was shown for the first time in imatinib resistant CML cells. Discussion: We show for the first time that Akirin-2 can be a novel biomarker in imatinib resistance. Targeting Akirin-2, NF kappa B and beta-catenin genes may provide an opportunity to overcome imatinib resistance in CML.