Roeder Ingo, Horn Matthias, Glauche Ingmar, Hochhaus Andreas, Mueller Martin C, Loeffler Markus
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, D-04107 Leipzig, Haertelstrasse 16-18, Germany.
Nat Med. 2006 Oct;12(10):1181-4. doi: 10.1038/nm1487. Epub 2006 Oct 1.
Treatment of chronic myeloid leukemia (CML) with the tyrosine kinase inhibitor imatinib represents a successful application of molecularly targeted cancer therapy. A rapid hematologic and cytogenetic response can be induced in the majority of people, even in advanced disease. However, complete eradication of malignant cells, which are characterized by the expression of the BCR-ABL1 fusion protein, is rare. Reasons for the persistence of the malignant clone are currently not known and provide a substantial challenge for clinicians and biologists. Based on a mathematical modeling approach that quantitatively explains a broad range of phenomena, we show for two independent datasets that clinically observed BCR-ABL1 transcript dynamics during imatinib treatment of CML can consistently be explained by a selective functional effect of imatinib on proliferative leukemia stem cells. Our results suggest the general potential of imatinib to induce a complete elimination of the malignant clone. Moreover, we predict that the therapeutic benefit of imatinib can, under certain circumstances, be accelerated by combination with proliferation-stimulating treatment strategies.
使用酪氨酸激酶抑制剂伊马替尼治疗慢性髓性白血病（CML）是分子靶向癌症治疗的成功应用。即使在晚期疾病中，大多数患者也能迅速产生血液学和细胞遗传学反应。然而，以BCR-ABL1融合蛋白表达为特征的恶性细胞的完全根除却很少见。恶性克隆持续存在的原因目前尚不清楚，这给临床医生和生物学家带来了巨大挑战。基于一种定量解释广泛现象的数学建模方法，我们对两个独立数据集表明，在伊马替尼治疗CML期间临床观察到的BCR-ABL1转录本动态可以通过伊马替尼对增殖性白血病干细胞的选择性功能作用得到一致解释。我们的结果表明伊马替尼具有诱导恶性克隆完全消除的总体潜力。此外，我们预测在某些情况下，伊马替尼与增殖刺激治疗策略联合使用可加速其治疗益处。
