Vaidya Shantashri, Vundinti Babu Rao, Shanmukhaiah Chandrakala, Chakrabarti Prantar, Ghosh Kanjaksha
Department of Cytogenetics, National Institute of Immunohaematology, 13th Floor, New Multistoried Building, KEM Hospital Campus, Parel, Mumbai, 400012, India.
Department of Haematology, 10th Floor, New Multistoried Building, KEM Hospital, Parel, Mumbai, 400012, India.
PLoS One. 2015 Jan 28;10(1):e0114828. doi: 10.1371/journal.pone.0114828. eCollection 2015.
Mutations in the ABL kinase domain and SH3-SH2 domain of the BCR/ABL gene and amplification of the Philadelphia chromosome are the two important BCR/ABL dependent mechanisms of imatinib resistance. Here, we intended to study the role played by TKI, imatinib, in selection of gene mutations and development of chromosomal abnormalities in Indian CML patients.
Direct sequencing methodology was employed to detect mutations and conventional cytogenetics was done to identify Philadelphia duplication.
Among the different mechanisms of imatinib resistance, kinase domain mutations (39%) of the BCR/ABL gene were seen to be more prevalent, followed by mutations in the SH3-SH2 domain (4%) and then BCR/ABL amplification with the least frequency (1%). The median duration of occurrence of mutation was significantly shorter for patients with front line imatinib than those pre-treated with hydroxyurea. Patients with high Sokal score (p = 0.003) showed significantly higher incidence of mutations, as compared to patients with low/intermediate score. Impact of mutations on the clinical outcome in AP and BC was observed to be insignificant. Of the 94 imatinib resistant patients, only 1 patient exhibited duplication of Philadelphia chromosome, suggesting a less frequent occurrence of this abnormality in Indian CML patients.
Close monitoring at regular intervals and proper analysis of the disease resistance would facilitate early detection of resistance and thus aid in the selection of the most appropriate therapy.
BCR/ABL基因的ABL激酶结构域和SH3-SH2结构域中的突变以及费城染色体的扩增是伊马替尼耐药的两个重要的BCR/ABL依赖性机制。在此，我们旨在研究酪氨酸激酶抑制剂（TKI）伊马替尼在印度慢性粒细胞白血病（CML）患者基因突变选择和染色体异常发生中的作用。
采用直接测序方法检测突变，并进行常规细胞遗传学分析以鉴定费城染色体重复。
在伊马替尼耐药的不同机制中，BCR/ABL基因的激酶结构域突变（39%）最为常见，其次是SH3-SH2结构域突变（4%），然后是BCR/ABL扩增，频率最低（1%）。一线使用伊马替尼的患者发生突变的中位时间明显短于羟基脲预处理的患者。与低/中度Sokal评分的患者相比，高Sokal评分的患者（p = 0.003）突变发生率显著更高。观察到突变对加速期（AP）和急变期（BC）临床结局的影响不显著。在94例伊马替尼耐药患者中，只有1例出现费城染色体重复，表明这种异常在印度CML患者中发生率较低。
定期密切监测并对耐药情况进行适当分析，将有助于早期发现耐药，从而有助于选择最合适的治疗方法。
