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20 May 2003 | Volume 138 Issue 10 | Pages 819-830
The Philadelphia chromosome translocation (t[9; 22]) results in the molecular juxtaposition of two genes, BCR and ABL, to form an aberrant BCR-ABL gene on chromosome 22. BCR-ABL is critical to the pathogenesis of chronic myelogenous leukemia and a subset of acute leukemias. The chimeric Bcr-Abl protein has constitutively elevated tyrosine phosphokinase activity. This abnormal enzymatic activation is critical to the oncogenic potential of Bcr-Abl. Initially, protein kinases were thought to be poor therapeutic targets because of their ubiquitous nature and crucial role in many normal physiologic processes. However, the advent of imatinib mesylate (Gleevec, Novartis Pharmaceuticals, Basel, Switzerland), formerly known as STI571 and CGP57148B, demonstrated that designer kinase inhibitors could be specific. This agent has shown striking activity in chronic myelogenous leukemia. It also inhibits phosphorylation of Kit (stem-cell factor receptor) and platelet-derived growth factor receptor. In addition, it has shown similar impressive responses, with little host toxicity, in gastrointestinal stromal tumors, which harbor activating Kit mutations, and in tumors with activated platelet-derived growth factor receptor. The studies of imatinib mesylate provide proof-of-principle for using aberrant kinases as a therapeutic target and are a model for the promise of molecular therapeutics. This paper reviews the current knowledge on the function of Bcr-Abl and its normal counterparts (Bcr and Abl), as well as the impact of this knowledge on the development of a remarkably successful targeted therapy approach.
For definitions of terms, see Glossary.
Author and Article Information
From University of Texas M.D. Anderson Cancer Center, Houston, Texas, and Oregon Health Sciences University, Portland, Oregon.
Potential Financial Conflicts of Interest:Consultancies: B.J. Druker (Novartis); Honoraria: B.J. Druker (Novartis), M. Talpaz (Novartis); Grants received: H.M. Kantarjian (Novartis).
Requests for Single Reprints: Razelle Kurzrock, MD, Department of Bioimmunotherapy, Box 422, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030; e-mail, rkurzroc{at}mdanderson.org.
Current Author Addresses: Drs. Kurzrock and Talpaz: University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 422, Houston, TX 77030.
Dr. Kantarjian: University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 428, Houston, TX 77030.
Dr. Druker: Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Mail Code L592, Portland, OR 97201. REVIEW
Philadelphia Chromosome–Positive Leukemias: From Basic Mechanisms to Molecular Therapeutics
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