III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany.
Haematologica. 2011 Mar;96(3):360-6. doi: 10.3324/haematol.2010.030999. Epub 2010 Dec 6.
Point mutations of the BCR-ABL tyrosine kinase domain are considered the predominant cause of imatinib resistance in chronic myeloid leukemia. The expansion of mutant BCR-ABL-positive clones under selective pressure of tyrosine kinase inhibition is referred to as clonal selection; there are few data on the reversibility of this phenomenon.
The changes of expression of mutant BCR-ABL-positive alleles after cessation of tyrosine kinase inhibitor treatment were examined in 19 patients with chronic myeloid leukemia harboring different mutations in a longitudinal follow-up. The proportion of mutant alleles was quantified by amplification of rearranged ABL sequences followed by mutation-specific restriction digestion, electrophoresis and densitometry. The size of mutant clones was established as a measure of the absolute amount of mutant cells considering the proportion of mutant BCR-ABL transcripts and the total level of BCR-ABL obtained by quantitative reverse transcriptase polymerase chain reaction.
The median proportion of mutant transcripts was 97% before and 8% after cessation of tyrosine kinase inhibitor treatment indicating a relative decline of 88% within a median of 6 months. The relative decrease in the size of the mutant clones was 86%. Repeated selection and deselection of the mutant clone after resumption and second cessation of tyrosine kinase inhibitor treatment was observed in individual patients.
Deselection of mutant BCR-ABL-positive clones after cessation of tyrosine kinase inhibitor treatment might be a common, rapid and reproducible phenomenon, although some patients harboring the T315I mutation showed no deselection. Cessation of tyrosine kinase inhibitor treatment may lead to the regression of T315I mutant clones to a level under the limit of detection, offering the therapeutic option of resumed tyrosine kinase inhibitor treatment under close surveillance of the mutation status.
BCR-ABL 酪氨酸激酶结构域的点突变被认为是慢性髓性白血病伊马替尼耐药的主要原因。在酪氨酸激酶抑制的选择压力下，突变型 BCR-ABL 阳性克隆的扩增被称为克隆选择；关于这种现象的可逆性，数据很少。
在 19 例慢性髓性白血病患者的纵向随访中，检测停止酪氨酸激酶抑制剂治疗后不同突变的表达变化。通过扩增重排 ABL 序列，然后进行突变特异性限制消化、电泳和密度计分析，检测突变型 BCR-ABL 阳性等位基因的表达变化。通过定量逆转录聚合酶链反应获得的 BCR-ABL 转录本的比例和总水平，将突变克隆的大小确定为突变细胞绝对数量的度量。
停止酪氨酸激酶抑制剂治疗前，突变转录本的中位数比例为 97%，治疗后为 8%，表明中位数为 6 个月内相对下降 88%。突变克隆大小的相对减少为 86%。在个别患者中，观察到在恢复和第二次停止酪氨酸激酶抑制剂治疗后，突变克隆的再次选择和去选择。
停止酪氨酸激酶抑制剂治疗后，突变型 BCR-ABL 阳性克隆的去选择可能是一种常见的、快速的和可重复的现象，尽管一些携带 T315I 突变的患者没有去选择。停止酪氨酸激酶抑制剂治疗可能导致 T315I 突变克隆回归到检测限以下的水平，为在密切监测突变状态的情况下恢复酪氨酸激酶抑制剂治疗提供了治疗选择。
