Cambier N, Chopra R, Strasser A, Metcalf D, Elefanty A G
The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Victoria, Australia.
Oncogene. 1998 Jan 22;16(3):335-48. doi: 10.1038/sj.onc.1201490.
The hallmark of chronic myeloid leukemia (CML) is the chimeric tyrosine kinase oncogene bcr-abl. Since expression of bcr-abl mRNA frequently increases with disease progression and a duplication of the Philadelphia chromosome (harbouring the bcr-abl hybrid locus) represents the most frequent karyotypic abnormality in acute phase CML, we hypothesized that the level of BCR-ABL protein may affect the disease phenotype. Therefore, the biological effects of high and low levels of BCR-ABL expression were compared in growth factor-dependent and -independent myeloid and lymphoid cell lines. Our results demonstrated that low levels of BCR - ABL were sufficient to render these cell lines growth factor independent and tumorigenic, but higher levels were mandatory for additional protection against apoptotic stimuli. The provision of growth factor or an activated ras oncogene did not afford the same degree of protection as high levels of BCR-ABL and there were qualitative differences between the survival signals mediated by BCR-ABL and Bcl-2. These results have enabled us to establish a dose-dependent hierarchy of BCR-ABL induced biological effects, thus distinguishing the activation of pathways mediating protection from cytokine withdrawal from those protecting against other apoptotic stimuli.
慢性髓性白血病（CML）的标志是嵌合型酪氨酸激酶致癌基因bcr-abl。由于bcr-abl mRNA的表达常常随疾病进展而增加，并且费城染色体（携带bcr-abl杂交位点）的重复是急性期CML中最常见的核型异常，我们推测BCR-ABL蛋白的水平可能影响疾病表型。因此，我们在依赖生长因子和不依赖生长因子的髓系及淋巴系细胞系中比较了高低水平BCR-ABL表达的生物学效应。我们的结果表明，低水平的BCR-ABL足以使这些细胞系不依赖生长因子并具有致瘤性，但更高水平对于抵御凋亡刺激是必需的。提供生长因子或激活的ras致癌基因所提供的保护程度不如高水平的BCR-ABL，并且BCR-ABL和Bcl-2介导的生存信号存在质的差异。这些结果使我们能够建立BCR-ABL诱导的生物学效应的剂量依赖性等级体系，从而区分介导抵御细胞因子撤除的信号通路激活与抵御其他凋亡刺激的信号通路激活。
