The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib.
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.
Department of Haematology, Hammersmith Hospitals Trust, Imperial College London, London, UK.
J S
JS
Khorashad
M
M
Anand
D
D
Marin
S
S
Saunders
T
T
Al-Jabary
A
A
Iqbal
S
S
Margerison
J V
JV
Melo
J M
JM
Goldman
J F
JF
Apperley
J
J
Kaeda
D000328:Adult; D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic / Q000235:genetics
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl