Abdul Aziz, Baba
(2012)
Molecular basis of primary and secondary
resistance to imatinib mesylate.
Other.
Pusat Pengajian Sains Perubatan.
(Submitted)
Abstract
Recently, IMATINffi MESYLATE (IM), a selective Tyrosine Kinase inhibitor, is widely used as a frontline
therapy for Chronic Myeloid Leukemia (CML). However, development of resistance to IM either primary or
secondary, has emerged as a major obstacle in the successful management of CML patients. Development of
resistance is a multifunctional phenomenon in patients with CML and is mediated by diversity of mechanisms
which could be classified under 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-ABLI and BCR-ABL gene amplification. The types and frequencies of mutation reported in different
studies have shown wide variability probably due to different composition of cohorts. But no reports are
available from Malaysia. So, this study was undertaken to investigate the frequency and pattern ofBCR-ABL
kinase domain mutations utilizing dHPLC, followed by direct sequencing and BCR-ABL gene amplification
using FISH on 92 CML patients who showed resistance to IM. Mutations were detected in 20 patients
(21.7%). Nine different types of mutations consisting of T315I (n=9), E255K (n=2), M351T (n=2), G250E
(n=2), E355G (n=l), Y253H (n=l), G251E (n=l), V289F (n=l) and N368S (n=l) mutation(s) respectively
were discovered in these patients. The T315I mutation appeared to be the most predominant type of mutation
among Malaysian CML patients. Interestingly, the G25IE and N368S were novel mutations which have not
been reported from elsewhere. In the rest 72 IM resistant CML patients, contribution of BCR-ABL gene
amplification was investigated, but none of them showed BCR-ABL gene amplification. It is presumed that
the mechanisms of resistance in these 72 patients might be due to BCR-ABL independent pathways for which
we are probing various candidate mechanisms, utilizing other grants. Different mutations confer different
levels of resistance and hence detection as well as characterization of TKD mutations is highly relevant to
guide therapy in CML patients. Furthermore we also tried to associate all the factors with the overall survival
among the CML patients treated with IM. The CML stage along with the presence of additional chromosomal
abnormalities (ACA) showed the most significant association with the overall survival of the patients. Thus,
performing conventional cytogenetics is still very crucial in identifYing the presence of ACA and
consequently help in predicting the prognosis of the patients.
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