Targeting the kinase activity of the BCR-ABL fusion protein in patients with chronic myeloid-leukemia

Francis J. Giles*, Jorge E. Cortes, Hagop M. Kantarjian

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

32 Scopus citations


Imatinib mesylate is a major advance in the therapy of patients with chronic myelogenous leukemia (CML). Imatinib mesylate binds to the inactive conformation of BCR-ABL tyrosine kinase suppressing the Philadelphia chromosome positive clone in CML. Clinical studies have yielded impressive results in all phases of CML. With higher rates of complete cytogenetic response with imatinib, molecular monitoring of disease is now advisable in assessing response and determining prognosis. Emergence of resistance to imatinib may be manifest at the hematologic, cytogenetic, or molecular levels in patients who remain in chronic phase, or may be evidenced by the development of more advanced CML phases. Resistance and eventual clinical failure of imatinib occurs in most patients with blastic phase disease. Resistance may occur at the level of Bcr-Abl, with reduction or loss of imatinib effectiveness as a kinase inhibitor, or, despite retention of its inhibitory ability, with changes in the ability to deliver an effective dose at the cellular level, and/or, the leukemia becoming less dependent on Bcr-Abl. The various mechanisms underlying these differing, non-mutually exclusive, mechanisms of resistance must be understood to develop corresponding therapeutic remedies. We review the current data on imatinib in CML, the criteria for diagnosis of imatinib resistance, and the mechanisms that underlie such resistance in CML.

Original languageEnglish (US)
Pages (from-to)615-623
Number of pages9
JournalCurrent Molecular Medicine
Issue number7
StatePublished - Nov 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology


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