Sattler M, Salgia R
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Cytokine Growth Factor Rev. 1997 Mar;8(1):63-79. doi: 10.1016/s1359-6101(96)00047-0.
BCR/ABL is a human chimeric oncogene that causes chronic myelogenous leukemia (CML). The BCR/ABL oncogene is generated from the Philadelphia chromosome (Ph) translocation, t(9;22)(q34;q11), and creates a constitutively active tyrosine kinase. There is clonal expansion of hematopoietic stem cells of several different lineages in CML. CML patients in stable phase usually have high white blood counts and immature cells of granulocytic lineages. Stable phase CML evolves to a more aggressive phase typically within 3.5-5 years, where differentiation is blocked and acute leukemia ensues. The transition of CML stable phase to blast phase is reflected in the loss of growth factor requirement of CML cells and correlates with additional cytogenetic alterations. Some biological effects reported in primary CML cells include reduced apoptosis and altered adhesion to fibronectin; however, the cells are dependent on hematopoietic growth factors. On a molecular level, the BCR/ABL translocation is well characterized. However, the actual mechanism of transformation by the BCR/ABL oncogene of hematopoietic cells is largely unknown. Enhancement of the c-ABL tyrosine kinase activity in BCR/ABL appears to be crucial for transformation. This tyrosine kinase activity leads to activation of several signal transduction pathways that are also utilized by hematopoietic growth factors, including steel factor, thrombopoietin, interleukin-3, and granulocyte/macrophage-colony stimulating factor. In several model systems, BCR/ABL has overlapping biological effects with hematopoietic growth factors, and transformation of hematopoietic growth factor-dependent cell lines leads to growth factor independence. In this review, we will describe the molecular and biological abnormalities in CML and several signal transduction mechanisms utilized by BCR/ABL as compared to hematopoietic growth factors.
BCR/ABL是一种导致慢性粒细胞白血病（CML）的人嵌合致癌基因。BCR/ABL致癌基因由费城染色体（Ph）易位t(9;22)(q34;q11)产生，并产生一种组成型活性酪氨酸激酶。CML中几种不同谱系的造血干细胞会发生克隆性扩增。稳定期的CML患者通常白细胞计数高，且有粒细胞谱系的未成熟细胞。CML稳定期通常在3.5至5年内演变为更具侵袭性的阶段，此时分化受阻，继而发展为急性白血病。CML稳定期向急变期的转变反映在CML细胞对生长因子需求的丧失，并与其他细胞遗传学改变相关。在原发性CML细胞中报道的一些生物学效应包括凋亡减少和对纤连蛋白的黏附改变；然而，这些细胞依赖造血生长因子。在分子水平上，BCR/ABL易位已得到充分表征。然而，BCR/ABL致癌基因转化造血细胞的实际机制在很大程度上尚不清楚。BCR/ABL中c-ABL酪氨酸激酶活性的增强似乎对转化至关重要。这种酪氨酸激酶活性导致几种信号转导途径的激活，造血生长因子也利用这些途径，包括干细胞因子、血小板生成素、白细胞介素-3和粒细胞/巨噬细胞集落刺激因子。在几个模型系统中，BCR/ABL与造血生长因子具有重叠的生物学效应，造血生长因子依赖性细胞系的转化导致生长因子非依赖性。在这篇综述中，我们将描述CML中的分子和生物学异常，以及与造血生长因子相比BCR/ABL利用的几种信号转导机制。
