The Presence of a BCR-ABL Mutant Allele in CML Does Not Always Explain Clinical Resistance to Imatinib

Leukemia. 2006 Apr;20(4):658-63. doi: 10.1038/sj.leu.2404137.

Abstract

The expansion of a leukemia clone bearing a Bcr-Abl kinase domain mutation is associated with acquired resistance to imatinib and may also predict disease progression in patients with Philadelphia-positive chronic myeloid leukemia (CML). Here we report results of pyrosequencing to quantitate the non-mutated and mutant alleles in 12 CML patients monitored over periods ranging from 11 to 58 months, and describe three contrasting kinetic patterns: Group 1 - in four patients total BCR-ABL transcript numbers remained high with the mutant allele predominating; Group 2 - in four patients the total number of BCR-ABL transcripts fell to low levels but the mutant allele predominated; and Group 3 - in four other patients the total level of transcripts remained high (n = 2) or fell (n = 2) but the mutant clone persisted at relatively low level. In Group 2 the mutant leukemia clone was presumably still relatively sensitive to imatinib but in Group 1 the leukemia could be classified as resistant. In Group 3 patients the imatinib sensitivity of the leukemia was variable. We conclude that a mutant clone does not necessarily have a proliferative advantage and its presence does not always account for resistance to imatinib. Other mechanisms underlie resistance in at least some patients.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Benzamides
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Fusion Proteins, bcr-abl / drug effects
  • Fusion Proteins, bcr-abl / genetics*
  • Humans
  • Imatinib Mesylate
  • Kinetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / diagnosis
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Male
  • Middle Aged
  • Mutation
  • Piperazines / pharmacology*
  • Piperazines / therapeutic use
  • Protein-Tyrosine Kinases / genetics
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Sensitivity and Specificity
  • Sequence Analysis, DNA
  • Transcription, Genetic / genetics

Substances

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