Barnes David J, Palaiologou Danai, Panousopoulou Eleni, Schultheis Beate, Yong Agnes S M, Wong Alice, Pattacini Laura, Goldman John M, Melo Junia V
Department of Haematology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
Cancer Res. 2005 Oct 1;65(19):8912-9. doi: 10.1158/0008-5472.CAN-05-0076.
Chronic myeloid leukemia (CML) starts with the acquisition of a BCR-ABL fusion gene in a single hematopoietic stem cell, but the time to progression is unpredictable. Although the tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of CML, its continuous administration is associated with development of resistance, particularly in advanced phase or blast crisis. We investigate here whether a feature of disease progression (i.e., elevated expression of Bcr-Abl in CD34+ progenitor cells from CML patients in blast crisis) has any bearing on the kinetics of resistance to imatinib. By studying cell lines that exogenously express Bcr-Abl over the range found from chronic phase to blast crisis of CML, we show that cells expressing high amounts of Bcr-Abl, as in blast crisis, are much less sensitive to imatinib and, more significantly, take a substantially shorter time for yielding a mutant subclone resistant to the inhibitor than cells with low expression levels, as in chronic phase. Our data suggest that the differential levels of the Bcr-Abl oncoprotein expressed by CD34+ CML cells may reflect the extent and duration of their response to imatinib; the relatively high levels of oncoprotein in advanced-phase disease may underlie the observed rapid development of resistance.
慢性髓性白血病（CML）始于单个造血干细胞中获得BCR-ABL融合基因，但其进展时间不可预测。尽管酪氨酸激酶抑制剂甲磺酸伊马替尼在治疗CML方面非常有效，但其持续给药与耐药性的产生有关，尤其是在晚期或急变期。我们在此研究疾病进展的一个特征（即急变期CML患者CD34+祖细胞中Bcr-Abl表达升高）是否与对伊马替尼耐药的动力学有关。通过研究在CML从慢性期到急变期所发现的范围内外源性表达Bcr-Abl的细胞系，我们发现，与急变期一样，表达大量Bcr-Abl的细胞对伊马替尼的敏感性要低得多，更重要的是，与慢性期低表达水平的细胞相比，产生对该抑制剂耐药的突变亚克隆所需的时间要短得多。我们的数据表明，CD34+CML细胞表达的Bcr-Abl癌蛋白水平差异可能反映了它们对伊马替尼反应的程度和持续时间；晚期疾病中相对较高水平的癌蛋白可能是观察到的耐药性快速发展的基础。
