Contribution of BCR-ABL kinase domain mutations to imatinib mesylate resistance in Philadelphia chromosome positive Malaysian chronic myeloid leukemia patients
Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is mediated by different mechanisms that can be classified as <em>BCR-ABL</em> dependent or <em>BCR-ABL</em> independent pathways. <em>BCR-ABL</em> dependent mechanisms...
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doaj-b7b979e16a3d497ca800ed97e603351e2020-11-25T03:51:09ZengPAGEPress PublicationsHematology Reports2038-83222038-83302012-11-0144e23e2310.4081/hr.2012.e232334Contribution of BCR-ABL kinase domain mutations to imatinib mesylate resistance in Philadelphia chromosome positive Malaysian chronic myeloid leukemia patientsMarjanu Hikmah Elias0Abdul Aziz Baba1Azlan Husin2Abu Dzarr Abdullah3Rosline Hassan4Goh Ai Sim5S. Fadilah Abdul Wahid6Ravindran Ankathil7Human Genome Centre, School of Medical Sciences, Health Campus, Universiti Sains MalaysiaHaemato-Oncology Unit, Department of Internal Medicine,Health Campus, Universiti Sains MalaysiaHaemato-Oncology Unit, Department of Internal Medicine,Health Campus, Universiti Sains MalaysiaHaemato-Oncology Unit, Department of Internal Medicine,Health Campus, Universiti Sains MalaysiaHematology Department, School of Medical Sciences, Health Campus, Universiti Sains MalaysiaHospital Pulau PinangMedicine Department and Cell Therapy Centre, UKM Medical CentreHuman Genome Centre, School of Medical Sciences, Health Campus, Universiti Sains MalaysiaDevelopment of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is mediated by different mechanisms that can be classified as <em>BCR-ABL</em> dependent or <em>BCR-ABL</em> independent pathways. <em>BCR-ABL</em> dependent mechanisms are most frequently associated with point mutations in tyrosine kinase domain (TKD) of <em>BCR-ABL1</em> and also with <em>BCR-ABL</em> 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 <em>BCR-ABL</em> kinase domain mutations using dHPLC followed by sequencing, and also status of <em>BCR-ABL</em> gene amplification using fluorescence <em>in situ</em> 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 <em>BCR-ABL</em> 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<em> BCR-ABL</em> 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.http://www.pagepress.org/journals/index.php/hr/article/view/4413chronic myeloid leukemia, imatinib mesylate, BCR-ABL dependent mechanisms, tyrosine kinase domain, mutation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marjanu Hikmah Elias Abdul Aziz Baba Azlan Husin Abu Dzarr Abdullah Rosline Hassan Goh Ai Sim S. Fadilah Abdul Wahid Ravindran Ankathil |
spellingShingle |
Marjanu Hikmah Elias Abdul Aziz Baba Azlan Husin Abu Dzarr Abdullah Rosline Hassan Goh Ai Sim S. Fadilah Abdul Wahid Ravindran Ankathil Contribution of BCR-ABL kinase domain mutations to imatinib mesylate resistance in Philadelphia chromosome positive Malaysian chronic myeloid leukemia patients Hematology Reports chronic myeloid leukemia, imatinib mesylate, BCR-ABL dependent mechanisms, tyrosine kinase domain, mutation |
author_facet |
Marjanu Hikmah Elias Abdul Aziz Baba Azlan Husin Abu Dzarr Abdullah Rosline Hassan Goh Ai Sim S. Fadilah Abdul Wahid Ravindran Ankathil |
author_sort |
Marjanu Hikmah Elias |
title |
Contribution of BCR-ABL kinase domain mutations to imatinib mesylate resistance in Philadelphia chromosome positive Malaysian chronic myeloid leukemia patients |
title_short |
Contribution of BCR-ABL kinase domain mutations to imatinib mesylate resistance in Philadelphia chromosome positive Malaysian chronic myeloid leukemia patients |
title_full |
Contribution of BCR-ABL kinase domain mutations to imatinib mesylate resistance in Philadelphia chromosome positive Malaysian chronic myeloid leukemia patients |
title_fullStr |
Contribution of BCR-ABL kinase domain mutations to imatinib mesylate resistance in Philadelphia chromosome positive Malaysian chronic myeloid leukemia patients |
title_full_unstemmed |
Contribution of BCR-ABL kinase domain mutations to imatinib mesylate resistance in Philadelphia chromosome positive Malaysian chronic myeloid leukemia patients |
title_sort |
contribution of bcr-abl kinase domain mutations to imatinib mesylate resistance in philadelphia chromosome positive malaysian chronic myeloid leukemia patients |
publisher |
PAGEPress Publications |
series |
Hematology Reports |
issn |
2038-8322 2038-8330 |
publishDate |
2012-11-01 |
description |
Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is mediated by different mechanisms that can be classified as <em>BCR-ABL</em> dependent or <em>BCR-ABL</em> independent pathways. <em>BCR-ABL</em> dependent mechanisms are most frequently associated with point mutations in tyrosine kinase domain (TKD) of <em>BCR-ABL1</em> and also with <em>BCR-ABL</em> 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 <em>BCR-ABL</em> kinase domain mutations using dHPLC followed by sequencing, and also status of <em>BCR-ABL</em> gene amplification using fluorescence <em>in situ</em> 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 <em>BCR-ABL</em> 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<em> BCR-ABL</em> 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. |
topic |
chronic myeloid leukemia, imatinib mesylate, BCR-ABL dependent mechanisms, tyrosine kinase domain, mutation |
url |
http://www.pagepress.org/journals/index.php/hr/article/view/4413 |
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