الفهرس 
Chronic myeloid leukemiaOnly 14 pages are availabe for public view
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Abstract
The current study investigated the mechanism of resistance to imatinib in chronic myeloid leukemia (CML) patients through screening for point mutations in the BCR-ABL kinase domain.
Examination of serial measurements of Abelson- breakpoint cluster region (BCR-ABL) mRNA in 100 CML patients treated with imatinib using real time quantitative - polymerase chain reaction (RQ-PCR) revealed that 19 patients achieved a complete molecular response (CMR), 53 patients achieved a major molecular response (MMR) and 12 patients achieved a suboptimal response to imatinib, whereas 16 patients showed resistance to imatinib.
The frequency of mutations in patients with increasing BCR-ABL transcript levels (n=16), and those with stable or decreasing levels (n=32) was determined using allele specific oligonucleotide - polymerase chain reaction (ASO-PCR). Fourteen out of the sixteen patients (87.5%) with > 2-fold rise in the BCR-ABL transcript levels had detectable mutations, whereas none of the 32 patients with stable or decreasing BCR-ABL transcript levels had any detectable mutation (P < 0.001).
The presence of a mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase / blast crisis (P < 0.001) and shorter survival (P < 0.001). Patients harboring P-loop mutations showed poor overall survival (P = 0.012) and progression free survival (P = 0.02) compared with patients harboring non-P-loop mutations. Patients carrying T315I mutation seemed to have a particularly poor outcome in terms of survival (P = 0.014), but not in terms of time to progression (P = 0.450) compared with patients harboring non-P-loop mutations.
These data suggest that a rise in BCR-ABL transcript levels of > 2-fold can be used as a primary indicator to test patients for BCR-ABL kinase domain mutations and that ASO-PCR is a valuable tool allowing a timely detection of mutations. Moreover, early detection of BCR-ABL mutations may play a role in identifying patients who are likely to become resistant to imatinib therapy, for whom alternative therapeutic options should be considered.