Characterizing of four common BCR-ABL kinase domain mutations [T315I, Y253H, M351T and E255K] in Iranian chronic myelogenous leukemia patients with imatinib resistance

ABSTRACT

Chronic myelogenous leukemia [CML] is a kind of hematopoietic stem-cell cancer. A significant number of CML patients who do not achieve an acceptable response to therapy, show acquired resistance against Imatinib. One of the most considerable causes of resistance against Imatinib as the first line of therapy, are BCR-ABL kinase domain mutations. One of the most considerable causes of resistance against Imatinib as the first line of therapy, are BCR-ABL kinase domain mutations. The study was performed on 39 CML patients with Imatinib resistance. Basic hematologic parameters in blood samples were checked to identify hematologic response. To identify molecular response, BCR-ABL/ABL ratio was assessed by Real-time PCR. The ABL kinase domain amplification was performed by PCR. Restriction fragment length polymorphism [RFLP] was performed to detect four common mutations [T315I, Y253H, E255K and M351T]. Finally the results were approved by direct sequencing. In this study, the Y253H mutation, detected by RFLP method and confirmed by direct sequencing, was the prevalent ABL kinase domain mutation in these 39 CML patients. The G250E, V379I and L384M mutations were found in three different cases with failure molecular response. CML patients with these four ABL kinase domain mutations cannot achieve major molecular response [MMR]. In addition, complete hematologic response [CHR] was observed only in the V379I mutated case and not in other mutated patients. Identification of ABL kinase domain mutations may be used as a proper and useful method for improving therapeutic strategies, avoiding delay in treatment and excessive expenditure in CML patients with Imatinib resistance