PP179. THE SEQUENCE ANALYSES OF IMATINIB MESYLATE BINDING SITE OF ABL KINASE DOMAIN IN SENSITIVE AND IMATINIB-RESISTANT HUMAN CML CELLS
YUSUF BARAN1,2, Ufuk Gündüz1, Besim Öğretmen2. 1. Middle East Technical University, Department of Biology, TURKEY; 2. Medical University of South Carolina, Department of Biochemistry and Molecular Biology, USA. e-mail: ybaran@metu.edu.tr
*Corresponding Author:
page: 128

Abstract

Imatinib is an anticancer agent which is commonly used for the treatment of chronic myeloid leukemia (CML). Imatinib specifically binds to 21 amino acid residues in ABL kinase domain resulting in stabilizing the inactive, non-ATP-binding form of ABL. Inhibition of the BCR-ABL kinase activity results in the transcriptional modulation of various genes involved in the control of the cell cycle, apoptosis, and cell growth, leading the Ph-positive cells to apoptotic death. Despite high rates of hematologic and cytogenetic responses, after exposure of imatinib, the emergence of resistance has been recognized as a major problem resulting in the overall poor efficacy of chemotherapy. Since the mutations in ABL kinase domain is crucial for the success of imatinib treatment, possible mutations which prevent imatinib binding to kinase domain were investigated. To determine whether a mutation in the ABL kinase domain was responsible for imatinib-resistance, total RNAs were isolated from sensitive and imatinib-resistant K562 and Meg-01 cells, converted to cDNA, and amplified by PCR using primers specific to imatinib binding region. The PCR products were eluted from agarose gel. The fragments encompassing the ATP-binding domain of the fusion protein were subjected to automated sequencing. The sequences were compared to the normal ABL gene sequence (Gene Bank accession number: M14752). The data revealed that there were no detectable mutations on imatinib binding site of BCR-ABL in any of imatinib-resistant cells. Therefore, it was concluded that the resistance to imatinib did not result from mutations in imatinib binding site but results of some other mechanisms.




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