Chronic myelogenous leukemia: from molecular biology to clinical aspects and novel targeted therapies.
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.
Inokuchi
Koiti
K
Division of Hematology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan. inokuchi@nms.ac.jp
D000818:Animals; D001549:Benzamides; D004195:Disease Models, Animal; D016313:Genes, abl / Q000235:genetics; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate