Sattler Martin, Scheijen Blanca, Weisberg Ellen, Griffin James D
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Adv Exp Med Biol. 2003;532:121-40. doi: 10.1007/978-1-4615-0081-0_11.
Tyrosine kinases are commonly mutated and activated in both acute and chronic myeloid leukemias. Here, we review the functions, signaling activities, mechanism of transformation, and therapeutic targeting of two prototypic tyrosine kinase oncogenes, BCR-ABL and FLT3, associated with chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), respectively. BCR-ABL is generated by the Philadelphia chromosome translocation between chromosomes 9 and 22, creating a chimeric oncogene in which the BCR and c-ABL genes are fused. The product of this oncogene, BCR-ABL, has elevated ABL tyrosine kinase activity and transforms hematopoietic cells by exerting a wide variety of biological effects, including reduction in growth factor dependence, enhanced viability, and altered adhesion of chronic myelocytic leukemia (CML) cells. Elevated tyrosine kinase activity of BCR-ABL is critical for activating downstream signalling cascades and for all aspects of transformation, explaining the remarkable clinical efficacy of the tyrosine kinase inhibitor, imatinib mesylate (STI571). By comparison, FLT3 is mutated in about one third of all cases of AML, most often through a mechanism that involves an internal tandem duplication (ITD) of a small number of amino acid residues in the juxtamembrane domain of the receptor. As is the case for BCR-ABL, these mutations activate the kinase activity constitutively, activate multiple signaling pathways, and result in an augmentation of proliferation and viability. Transformation by FLT3-ITD can readily be observed in murine models, and FLT3 cooperates with other types of oncogenes to create a fully transformed acute leukemia. FLT3 tyrosine kinase inhibitors are currently being evaluated in clinical trials and may be very useful therapeutic agents in AML.
酪氨酸激酶在急性和慢性髓系白血病中通常发生突变并被激活。在此，我们综述了分别与慢性髓系白血病（CML）和急性髓系白血病（AML）相关的两个典型酪氨酸激酶癌基因BCR-ABL和FLT3的功能、信号传导活性、转化机制及治疗靶向。BCR-ABL由9号和22号染色体之间的费城染色体易位产生，形成一个嵌合癌基因，其中BCR和c-ABL基因融合。该癌基因的产物BCR-ABL具有升高的ABL酪氨酸激酶活性，并通过发挥多种生物学效应来转化造血细胞，包括降低对生长因子的依赖性、增强生存能力以及改变慢性髓性白血病（CML）细胞的黏附。BCR-ABL升高的酪氨酸激酶活性对于激活下游信号级联反应和转化的各个方面都至关重要，这解释了酪氨酸激酶抑制剂甲磺酸伊马替尼（STI571）显著的临床疗效。相比之下，约三分之一的AML病例中FLT3发生突变，最常见的机制是受体近膜结构域中少数氨基酸残基的内部串联重复（ITD）。与BCR-ABL的情况一样，这些突变组成性地激活激酶活性，激活多个信号通路，并导致增殖和生存能力增强。在小鼠模型中很容易观察到FLT3-ITD介导的转化，并且FLT3与其他类型的癌基因协同作用以形成完全转化的急性白血病。FLT3酪氨酸激酶抑制剂目前正在临床试验中进行评估，可能是AML中非常有用的治疗药物。
