title: Mutations of the BCR-ABL-kinase domain occur in a minority of patients with stable complete cytogenetic response to imatinib.
abstract: Residual leukemia is demonstrable by reverse transcriptase-polymerase chain reaction in most patients with chronic myeloid leukemia who obtain a complete cytogenetic response (CCR) to imatinib. In patients who relapse during imatinib therapy, a high rate of mutations in the kinase domain of BCR-ABL have been identified, but the mechanisms underlying disease persistence in patients with a CCR are poorly characterized. To test whether kinase domain mutations are a common mechanism of disease persistence, we studied patients in stable CCR. Mutations were demonstrated in eight of 42 (19%) patients with successful amplification and sequencing of BCR-ABL. Mutation types were those commonly associated with acquired drug resistance. Four patients with mutations had a concomitant rise of BCR-ABL transcript levels, two of whom subsequently relapsed; the remaining four did not have an increase in transcript levels and follow-up samples, when amplifiable, were wild type. BCR-ABL-kinase domain mutations in patients with a stable CCR are infrequent, and their detection does not consistently predict relapse. Alternative mechanisms must be responsible for disease persistence in the majority of patients.
authors.affiliation: Cell and Developmental Biology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Sherbenou
authors.forename: M J
authors.initials: MJ
authors.lastname: Wong
authors.forename: A
authors.initials: A
authors.lastname: Humayun
authors.forename: L S
authors.initials: LS
authors.lastname: McGreevey
authors.forename: P
authors.initials: P
authors.lastname: Harrell
authors.forename: R
authors.initials: R
authors.lastname: Yang
authors.forename: M
authors.initials: M
authors.lastname: Mauro
authors.forename: M C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: R D
authors.initials: RD
authors.lastname: Press
authors.forename: B J
authors.initials: BJ
authors.lastname: Druker
authors.forename: M W
authors.initials: MW
authors.lastname: Deininger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D002851:Chromatography, High Pressure Liquid; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016312:Treatment Refusal
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D003062:Codon; D004273:DNA, Neoplasm; D050505:Mutant Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl