Abstract
Imatinib mesylate is a selective Bcr/Abl kinase inhibitor and an effective anticancer agent for Bcr/Abl-positive chronic myelogenous leukemia. Most patients in chronic phase maintain durable responses; however, many in blast crisis fail to respond, or relapse quickly. Mutations within the BCR/ABL kinase domain are the most commonly identified mechanism associated with relapse. To overcome the imatinib resistance in CML, many investigators have tried to clarify molecular mechanism for imatinib resistance in cells of patients who failed to respond to imatinib. Our aim was to invesitigate underlying mechanism for imatinib resistance in SR-1 cells, which were derived from a CML patient in blast crisis. We detected the new mutation of BCR/ABL, resulting in premature termination and loss of BCR/ABL fusion protein expression, which might be possible mechanism for the resistance to imatinib in SR-1 cells.
Highlights
Chronic myelogenous leukemia (CML) is a hematopoietic stem cell malignancy characterized by the t (9;22) chromosomal translocation resulting in the formation of the BCR/ABL fusion gene
Imatinib resistance can be caused by mutations in the BCR/ ABL kinase domain resulting in interference with imatinib binding, and BCR/ABL amplification and/or increased Bcr/Abl protein expression (Gorre et al, 2001; Shah et al, 2002)
We established SR-1 cells from a CML patient in blast crisis. It has not been evaluated the molecular mechanism for imatinib resistance in SR-1 cells
Summary
Chronic myelogenous leukemia (CML) is a hematopoietic stem cell malignancy characterized by the t (9;22) chromosomal translocation resulting in the formation of the BCR/ABL fusion gene. The BCR/ ABL gene is known to be essential to the pathogenesis of CML. The BCR/ABL gene product demonstrates constitutively activated tyrosine kinase activity. CML invariably progresses from an initial chronic phase to an accelerated phase and terminal blast crisis (Lugo et al, 1990). Imatinib mesylate (STI571) is a 2-phenylamine pyrimidine that targets the ATP-binding site of the kinase domain of Abl (Schindler et al, 2000). Imatinib has known to be highly effective in the treatment of CML (Kantarjian et al, 2002). The emergence of resistance to imatinib has been the unresolved problems in treating CML
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