Steelman L S, Pohnert S C, Shelton J G, Franklin R A, Bertrand F E, McCubrey J A
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.
Leukemia. 2004 Feb;18(2):189-218. doi: 10.1038/sj.leu.2403241.
The roles of the JAK/STAT, Raf/MEK/ERK and PI3K/Akt signal transduction pathways and the BCR-ABL oncoprotein in leukemogenesis and their importance in the regulation of cell cycle progression and apoptosis are discussed in this review. These pathways have evolved regulatory proteins, which serve to limit their proliferative and antiapoptotic effects. Small molecular weight cell membrane-permeable drugs that target these pathways have been developed for leukemia therapy. One such example is imatinib mesylate, which targets the BCR-ABL kinase as well as a few structurally related kinases. This drug has proven to be effective in the treatment of CML patients. However, leukemic cells have evolved mechanisms to become resistant to this drug. A means to combat drug resistance is to target other prominent signaling components involved in the pathway or to inhibit BCR-ABL by other mechanisms. Treatment of imatinib-resistant leukemia cells with drugs that target Ras (farnysyl transferase inhibitors) or with the protein destabilizer geldanamycin has proven to be a means to inhibit the growth of resistant cells. This review will tie together three important signal transduction pathways involved in the regulation of hematopoietic cell growth and indicate how their expression is dysregulated by the BCR-ABL oncoprotein.
本综述讨论了JAK/STAT、Raf/MEK/ERK和PI3K/Akt信号转导通路以及BCR-ABL癌蛋白在白血病发生中的作用，及其在调节细胞周期进程和细胞凋亡中的重要性。这些通路进化出了调节蛋白，用于限制其增殖和抗凋亡作用。针对这些通路的小分子细胞膜通透性药物已被开发用于白血病治疗。甲磺酸伊马替尼就是这样一个例子，它靶向BCR-ABL激酶以及一些结构相关的激酶。这种药物已被证明对治疗慢性粒细胞白血病患者有效。然而，白血病细胞已经进化出对这种药物产生耐药性的机制。对抗耐药性的一种方法是靶向该通路中其他突出的信号成分，或通过其他机制抑制BCR-ABL。用靶向Ras的药物（法尼基转移酶抑制剂）或蛋白稳定剂格尔德霉素治疗伊马替尼耐药的白血病细胞已被证明是抑制耐药细胞生长的一种方法。本综述将把参与造血细胞生长调节的三条重要信号转导通路联系起来，并指出它们的表达是如何被BCR-ABL癌蛋白失调的。
