Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia

Cancer Cell. 2002 Aug;2(2):117-25. doi: 10.1016/s1535-6108(02)00096-x.


Through sequencing analysis of blood or bone marrow samples from patients with chronic myeloid leukemia, we identified BCR-ABL kinase domain mutations in 29 of 32 patients whose disease relapsed after an initial response to the tyrosine kinase inhibitor imatinib. Fifteen different amino acid substitutions affecting 13 residues in the kinase domain were found. Mutations fell into two groups-those that alter amino acids that directly contact imatinib and those postulated to prevent BCR-ABL from achieving the inactive conformational state required for imatinib binding. Distinct mutations conferred varying degrees of imatinib resistance. Mutations detected in a subset of patients with stable chronic phase disease correlated with subsequent disease progression. Multiple independent mutant clones were detected in a subset of relapsed cases. Our data support a clonal selection model of preexisting BCR-ABL mutations that confer imatinib resistance.

Publication types

  • Comment
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / therapeutic use*
  • Benzamides
  • Clinical Trials as Topic
  • Clone Cells / metabolism
  • Clone Cells / pathology
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm*
  • Fusion Proteins, bcr-abl / chemistry*
  • Fusion Proteins, bcr-abl / genetics*
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Models, Molecular
  • Mutation*
  • Neoplasm Recurrence, Local
  • Piperazines / administration & dosage
  • Piperazines / therapeutic use*
  • Protein Structure, Tertiary
  • Pyrimidines / administration & dosage
  • Pyrimidines / therapeutic use*
  • Recurrence
  • Time Factors


  • Antineoplastic Agents
  • Benzamides
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl