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Philadelphia Chromosome–Positive Leukemias: From Basic Mechanisms to Molecular Therapeutics

Razelle Kurzrock, MD; Hagop M. Kantarjian, MD; Brian J. Druker, MD; and Moshe Talpaz, MD
[+] Article and Author 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@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.


Ann Intern Med. 2003;138(10):819-830. doi:10.7326/0003-4819-138-10-200305200-00010
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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.

Figures

Grahic Jump Location
Figure 1.
The normal Bcr and Abl proteins and the various aberrant Bcr-Abl counterparts.GEFGAPSH2Grb-2XPBNY393F401PXXPNLSNESAtmcdc2PKC

Functional sites in the Bcr protein include a serine and threonine kinase domain in exon 1, a central guanine exchange factor ( ) domain, and a carboxy-terminal guanosine triphosphatase–activating protein ( ) domain. Src homology-2 ( )–binding sites are also present in exon 1. The Bcr-associated protein (Bap-1) interacts with the more distal of these sites. Growth factor receptor–bound protein 2 ( ) associates with the proximal SH2-binding site containing a phosphotyrosine in position 177. Abl interacts with the second and third SH2 binding sites. The GEF domain interacts with the xeroderma pigmentosum B ( ) DNA repair protein. The normal Abl protein contains three SH domains near the -terminal. The tyrosine at position 393 ( ) is the major site of autophosphorylation within the kinase domain. Phenylalanine 401 ( ) is highly conserved in protein tyrosine kinases containing SH3 domains. The central area of the protein has proline-rich regions ( ) capable of binding to SH3 domains and a nuclear localization signal ( ). The carboxy-terminus contains DNA as well as G- and F-actin–binding domains, a nuclear export signal ( ), and nuclear localization signals. The phosphorylation sites by , , and protein kinase C ( ) are depicted. At the bottom of the figure, various Bcr-Abl proteins and their junction breakpoints are shown. Ragged red lines indicate breakpoints in Bcr and Abl.

Grahic Jump Location
Grahic Jump Location
Figure 2.
The mechanism of action of imatinib mesylate.A.ATPB.

The Bcr-Abl tyrosine phosphokinase enzyme is constitutively active. Adenosine triphosphate ( ) is an energy molecule used to drive Bcr-Abl enzymatic function. The enzyme's tyrosine kinase function is carried out at the kinase pocket. Bcr-Abl binds ATP and transfers phosphate from ATP to tyrosine residues on its substrates, thereby transmitting intracellular signals independently of ligand binding to growth factor receptors, such as that for interleukin-3. When imatinib mesylate (STI571) occupies the kinase pocket, it blocks the action of ATP, thereby suppressing phosphorylation of downstream effector molecules. ADP = adenosine diphosphate.

Grahic Jump Location
Grahic Jump Location
Figure 3.
p210-encoding Bcr-Abl signaling pathways.FakMAPKs

Bcr-Abl interacts with the interleukin-3 receptor β(c) subunit and constitutively induces its phosphorylation. Downstream signaling occurs independently of ligand binding. Adaptor molecules connect Bcr-Abl to Ras and PI-3 kinase pathways; to focal adhesion complexes (affected molecules include focal adhesion kinase [ ], paxillin, and actin cytoskeleton); and to messenger systems, such as Jak-Stat (Janus kinase signal transducer and activator of transcription) kinases. Downstream effectors involve mitogen-activated protein kinases ( ) and survival proteins interacting with the Bcl-2 family. GDP = guanosine diphosphate; GEF = guanine exchange factor; GTP = guanosine triphosphate; NES = nuclear export signal; NLS = nuclear localization signal; PI-3 = phosphatidylinosital-3; SOS = son of sevenless; XPB = xeroderma pigmentosum B.

Grahic Jump Location

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