Inokuchi Koiti
Division of Hematology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
J Nippon Med Sch. 2006 Aug;73(4):178-92. doi: 10.1272/jnms.73.178.
The critical causative event in chronic myelogenous leukemia (CML) is the fusion of the head of the bcr gene with the body of the abl gene, named bcr/abl gene. This chimeric BCR/ABL molecule transforms primary myeloid cells to leukemic cells and induces a CML-like disease in mice. The mouse CML model expressing the BCR/ABL molecule has provided important new insights into the molecular pathophysiology of CML and has directly answered many questions regarding this disease. Furthermore, numerous clinical studies have demonstrated a correlation between leukemic clinical features and the position of the breakpoint in the BCR gene of the chimeric BCR/ABL gene. Understanding of the molecular pathogenesis of CML has led to the development of several novel therapies. The BCR/ABL molecule is unique oncogeneiety, having ABL tyrosine kinase activity, making it an ideal target for drug development. Subsequent clinical studies now realize the hypothesis that selective inhibition of the abl tyrosine kinase activity using imatinib mesylate might be useful for the treatment of CML. This article reviews the history of BCR/ABL molecular biology, including the CML model mouse, clinical molecular studies and the recent findings of imatinib mesylate and more potent tyrosine kinase inhibitors developed for the treatment of CML.
慢性粒细胞白血病（CML）中的关键致病事件是bcr基因的头部与abl基因的主体融合，即bcr/abl基因。这种嵌合的BCR/ABL分子将原代髓细胞转化为白血病细胞，并在小鼠中诱发类似CML的疾病。表达BCR/ABL分子的小鼠CML模型为CML的分子病理生理学提供了重要的新见解，并直接回答了许多关于该疾病的问题。此外，大量临床研究表明白血病临床特征与嵌合BCR/ABL基因的BCR基因中断点位置之间存在关联。对CML分子发病机制的理解促使了几种新疗法的开发。BCR/ABL分子具有独特的致癌性，具有ABL酪氨酸激酶活性，使其成为药物开发的理想靶点。随后的临床研究证实了使用甲磺酸伊马替尼选择性抑制abl酪氨酸激酶活性可能对CML治疗有用的假设。本文回顾了BCR/ABL分子生物学的历史，包括CML模型小鼠、临床分子研究以及甲磺酸伊马替尼和为治疗CML开发的更有效的酪氨酸激酶抑制剂的最新研究结果。
