Nishii K, Kabarowski J H, Gibbons D L, Griffiths S D, Titley I, Wiedemann L M, Greaves M F
Leukaemia Research Fund Centre, Institute of Cancer Research, London, UK.
Oncogene. 1996 Nov 21;13(10):2225-34.
Using a temperature-sensitive mutant of the p210 BCR-ABL gene, transfected into a growth factor-dependent cell line (BaF3), we show that transient BCR-ABL kinase expression increases single cell and clonogenic resistance to apoptosis arising from genotoxic damage induced by ionizing radiation and VP-16/etoposide. This effect is achieved in the absence of any detectable changes in the levels of BCL-2, BAX or BCL-x proteins and is independent of proliferative, MAP kinase-dependent effects of BCR-ABL kinase. In contrast to parental cells that transiently arrest in G2 and then apoptose, p210 BaF3 cells show a pronounced and sustained G2 arrest following radiation coupled with enhanced phosphorylation of cdc2. A cell cycle block in early M phase induced by the mitotic spindle poison, nocodazole, does not provide protection from apoptosis. Reversal of G2 arrest by caffeine abolishes the protective effect of BCR-ABL kinase. These data provide further insight into the transforming properties of BCR-ABL and are relevant to the clinical intransigence of Ph-positive leukaemias.
利用一种对温度敏感的p210 BCR-ABL基因突变体，将其转染到一种依赖生长因子的细胞系（BaF3）中，我们发现短暂的BCR-ABL激酶表达可增强单细胞和克隆形成对电离辐射及VP-16/依托泊苷诱导的基因毒性损伤所引发的凋亡的抗性。这种效应在BCL-2、BAX或BCL-x蛋白水平未出现任何可检测到的变化的情况下实现，并且独立于BCR-ABL激酶的增殖性、丝裂原活化蛋白激酶依赖性效应。与短暂停滞在G2期然后发生凋亡的亲代细胞不同，p210 BaF3细胞在辐射后表现出明显且持续的G2期停滞，同时伴有cdc2磷酸化增强。由有丝分裂纺锤体毒物诺考达唑诱导的早期M期细胞周期阻滞并不能提供抗凋亡保护。咖啡因逆转G2期停滞可消除BCR-ABL激酶的保护作用。这些数据为深入了解BCR-ABL的转化特性提供了更多信息，并且与Ph阳性白血病的临床难治性相关。
