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

Razelle Kurzrock, Hagop M. Kantarjian, Brian Druker, Moshe Talpaz

Research output: Contribution to journalArticle

238 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)819-830
Number of pages12
JournalAnnals of Internal Medicine
Volume138
Issue number10
StatePublished - May 20 2003
Externally publishedYes

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Philadelphia Chromosome
Leukemia
Platelet-Derived Growth Factor Receptors
Phosphotransferases
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Proto-Oncogene Proteins c-kit
Therapeutics
Chromosomes, Human, Pair 22
Gastrointestinal Stromal Tumors
Molecular Models
Switzerland
Protein Kinases
Genes
Tyrosine
Phosphorylation
Imatinib Mesylate
Mutation
Pharmaceutical Preparations
Neoplasms
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Philadelphia Chromosome-Positive Leukemias : From Basic Mechanisms to Molecular Therapeutics. / Kurzrock, Razelle; Kantarjian, Hagop M.; Druker, Brian; Talpaz, Moshe.

In: Annals of Internal Medicine, Vol. 138, No. 10, 20.05.2003, p. 819-830.

Research output: Contribution to journalArticle

Kurzrock, Razelle ; Kantarjian, Hagop M. ; Druker, Brian ; Talpaz, Moshe. / Philadelphia Chromosome-Positive Leukemias : From Basic Mechanisms to Molecular Therapeutics. In: Annals of Internal Medicine. 2003 ; Vol. 138, No. 10. pp. 819-830.
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