Rejali Leili, Poopak Behzad, Hasanzad Mandana, Sheikhsofla Fatemeh, Varnoosfaderani Ameneh Saadat, Safari Nazila, Rabieipoor Saghar
MSc in Molecular Genetics, Islamic Azad University, Tehran Medical Sciences Branch, Tehran, IR Iran.
DCLS, PhD in Hematology, Islamic Azad University, Tehran Medical Sciences Branch, Tehran, IR Iran.
Iran J Cancer Prev. 2015 May;8(3):e2334. doi: 10.17795/ijcp2334. Epub 2015 May 27.
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.
慢性粒细胞白血病（CML）是一种造血干细胞癌症。相当数量的CML患者对治疗未取得可接受的反应，表现出对伊马替尼的获得性耐药。作为一线治疗，对伊马替尼耐药的最主要原因之一是BCR-ABL激酶结构域突变。
作为一线治疗，对伊马替尼耐药的最主要原因之一是BCR-ABL激酶结构域突变。
对39例对伊马替尼耐药的CML患者进行了研究。检查血样中的基本血液学参数以确定血液学反应。为确定分子反应，通过实时PCR评估BCR-ABL/ABL比值。通过PCR进行ABL激酶结构域扩增。采用限制性片段长度多态性（RFLP）检测四种常见突变（T315I、Y253H、E255K和M351T）。最后通过直接测序验证结果。
在本研究中，通过RFLP方法检测并经直接测序证实的Y253H突变是这39例CML患者中普遍存在的ABL激酶结构域突变。在三例分子反应失败的不同病例中发现了G250E、V379I和L384M突变。具有这四种ABL激酶结构域突变的CML患者无法实现主要分子反应（MMR）。此外，仅在V379I突变病例中观察到完全血液学反应（CHR），其他突变患者未观察到。
鉴定ABL激酶结构域突变可作为一种合适且有用的方法，用于改进治疗策略，避免伊马替尼耐药的CML患者治疗延误和费用过高。
