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.
Khorashad
J S
JS
Department of Haematology, Hammersmith Hospitals Trust, Imperial College London, London, UK.
Anand
M
M
Marin
D
D
Saunders
S
S
Al-Jabary
T
T
Iqbal
A
A
Margerison
S
S
Melo
J V
JV
Goldman
J M
JM
Apperley
J F
JF
Kaeda
J
J
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