Bagadi Sarita, Saikia Tapan, Pany Ayaskant, Das Bibhu
Research and Development, Super Religare Laboratories, Mumbai, India.
Clin Lab. 2011;57(7-8):619-23.
The current study was undertaken to find out the frequency and distribution of ABL kinase domain (KD) mutations showing resistance to tyrosine kinase inhibitors (TKI) in CML patients from India.
A total of 24 TKI resistant CML patients were screened for ABL KD mutation by semi-nested reverse transcription PCR and sequencing. The expression of BCR-ABL transcripts was quantified by Real Time Taqman assay.
Sixteen different point mutations were detected in 14 (58.3%) of 24 TKI resistant patients. Five out of the 16 mutations were located at the four hot spots of ABL kinase domain: one at the P-loop (Q252H), one at the imatinib binding site (T315I), two at the catalytic domain (M351, Y353F) and one at the active A loop (H396P). The three mutations, viz. M244V, T315I and A380V, were the most frequent mutations and accounted for 40.9% of all resistance associated mutations.
In the present study, the presence of ABL KD mutations was found to be a major cause of drug resistance. The T315I mutation was found to be resistant to second generation drugs such as dasatinib. The study reinforces the need for new therapeutic options which can target this mutation.
本研究旨在查明印度慢性粒细胞白血病（CML）患者中对酪氨酸激酶抑制剂（TKI）耐药的ABL激酶结构域（KD）突变的频率和分布情况。
通过半巢式逆转录PCR和测序对总共24例对TKI耐药的CML患者进行ABL KD突变筛查。采用实时Taqman分析法对BCR-ABL转录本的表达进行定量分析。
在24例对TKI耐药的患者中，有14例（58.3%）检测到16种不同的点突变。16种突变中有5种位于ABL激酶结构域的4个热点区域：1种位于P环（Q252H），1种位于伊马替尼结合位点（T315I），2种位于催化结构域（M351、Y353F），1种位于活性A环（H396P）。M244V、T315I和A380V这3种突变是最常见的突变，占所有耐药相关突变的40.9%。
在本研究中，发现ABL KD突变的存在是耐药的主要原因。发现T315I突变对达沙替尼等第二代药物耐药。该研究强化了对能够靶向此突变的新治疗方案的需求。
