Abstract
Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is mediated by different mechanisms that can be classified as BCR-ABL dependent or BCR-ABL independent pathways. BCR-ABL dependent mechanisms are most frequently associated with point mutations in tyrosine kinase domain (TKD) of BCR-ABL1 and also with BCR-ABL gene amplification. Many different types and frequencies of mutations have been reported in different studies, probably due to the different composition of study cohorts. Since no reports are available from Malaysia, this study was undertaken to investigate the frequency and pattern of BCR-ABL kinase domain mutations using dHPLC followed by sequencing, and also status of BCR-ABL gene amplification using fluorescence in situ hybridization (FISH) on 40 IM resistant Malaysian CML patients. Mutations were detected in 13 patients (32.5%). Five different types of mutations (T315I, E255K, Y253H, M351T, V289F) were identified in these patients. In the remaining 27 IM resistant CML patients, we investigated the contribution made by BCR-ABL gene amplification, but none of these patients showed amplification. It is presumed that the mechanisms of resistance in these 27 patients might be due to BCR-ABL independent pathways. Different mutations confer different levels of resistance and, therefore, detection and characterization of TKD mutations is highly important in order to guide therapy in CML patients.
Highlights
Imatinib mesylate (IM) is used as a frontline therapy for chronic myeloid leukemia (CML) as it is highly effective in the treatment and management of Philadelphia (Ph) positive CML patients
As IM binds to the adenosine triphosphate (ATP) binding site
In the remaining 27 IM resistant CML BCR-ABL gene,[6] as well as amplification and gene amplification by FISH on 40 Malaysian patients, we investigated the contribution overexpression of the BCR-ABL gene locus.[7]
Summary
Imatinib mesylate (IM) is used as a frontline therapy for chronic myeloid leukemia (CML) as it is highly effective in the treatment and management of Philadelphia (Ph) positive CML patients. Since no reports are available - from Malaysia, this study was undertaken to n investigate the frequency and pattern of BCRo ABL kinase domain mutations using dHPLC N followed by sequencing, and status of kinase protein semi-competitively. Y253H, M351T, V289F) were identified in these in the tyrosine kinase domain (TKD) of the domain mutations using dHPLC and BCR-ABL patients. Different muta- identified in the tyrosine kinase domain of the tions confer different levels of resistance and, BCR-ABL gene.[8] Different studies have report- Study subjects detection and characterization of ed a broad range of frequencies of mutations The study was undertaken at Universiti. Extended access protocols, and who showed GEN, Germany) according to the manufacturonly suboptimal response or signs of clinical er’s instructions with a slight modification, folresponse to IM Those CML patients who were lowed by cDNA synthesis using the cDNA Results. Tics and treatment management of the chronic myeloid leukemia patients
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