Khorashad J S, Anand M, Marin D, Saunders S, Al-Jabary T, Iqbal A, Margerison S, Melo J V, Goldman J M, Apperley J F, Kaeda J
Department of Haematology, Hammersmith Hospitals Trust, Imperial College London, London, UK.
Leukemia. 2006 Apr;20(4):658-63. doi: 10.1038/sj.leu.2404137.
The expansion of a leukemia clone bearing a Bcr-Abl kinase domain mutation is associated with acquired resistance to imatinib and may also predict disease progression in patients with Philadelphia-positive chronic myeloid leukemia (CML). Here we report results of pyrosequencing to quantitate the non-mutated and mutant alleles in 12 CML patients monitored over periods ranging from 11 to 58 months, and describe three contrasting kinetic patterns: Group 1 - in four patients total BCR-ABL transcript numbers remained high with the mutant allele predominating; Group 2 - in four patients the total number of BCR-ABL transcripts fell to low levels but the mutant allele predominated; and Group 3 - in four other patients the total level of transcripts remained high (n = 2) or fell (n = 2) but the mutant clone persisted at relatively low level. In Group 2 the mutant leukemia clone was presumably still relatively sensitive to imatinib but in Group 1 the leukemia could be classified as resistant. In Group 3 patients the imatinib sensitivity of the leukemia was variable. We conclude that a mutant clone does not necessarily have a proliferative advantage and its presence does not always account for resistance to imatinib. Other mechanisms underlie resistance in at least some patients.
携带Bcr-Abl激酶结构域突变的白血病克隆的扩增与对伊马替尼产生获得性耐药相关，并且还可能预测费城染色体阳性慢性髓性白血病（CML）患者的疾病进展。在此，我们报告了焦磷酸测序结果，以定量分析12例CML患者在11至58个月期间监测到的非突变和突变等位基因，并描述了三种截然不同的动力学模式：第1组 - 4例患者中，BCR-ABL转录本总数保持在高水平，且突变等位基因占主导；第2组 - 4例患者中，BCR-ABL转录本总数降至低水平，但突变等位基因占主导；第3组 - 另外4例患者中，转录本总水平保持在高水平（2例）或下降（2例），但突变克隆以相对较低水平持续存在。在第2组中，突变白血病克隆可能仍对伊马替尼相对敏感，但在第1组中，白血病可归类为耐药。在第3组患者中，白血病对伊马替尼的敏感性各不相同。我们得出结论，突变克隆不一定具有增殖优势，其存在也并不总是导致对伊马替尼耐药。至少在一些患者中，其他机制是耐药的基础。
