title: A single nucleotide polymorphism in the coding region of ABL and its effects on sensitivity to imatinib.
abstract: We have identified a gene polymorphism (K247R) within or close to the P-loop of BCR-ABL, which leads to the substitution of arginine for lysine. We investigated the allelic frequency of K247R by screening 157 CML patients and 213 healthy blood donors with conventional sequencing, restriction enzyme digest and single strand conformational polymorphism analysis, and found the arginine allele to be rare. Three out of five CML patients with the arginine allele of K247R failed to achieve a major cytogenetic response to imatinib, suggesting that the arginine allele may have reduced sensitivity. However, despite K247R's position in or near to the P-loop, biochemical and cellular assays of imatinib and dasatinib sensitivity showed no alteration compared to wild type. Clinicians should be aware that possession of the arginine allele of K247R does not reflect a mutation that necessitates a change in the therapeutic strategy, unless there are other signs of inadequate response to drug.
authors.affiliation: Oregon Health & Science University Cancer Institute, Portland, OR, USA. l.c.crossman@ncl.ac.uk
authors.forename: L C
authors.initials: LC
authors.lastname: Crossman
authors.forename: T
authors.initials: T
authors.lastname: O'Hare
authors.forename: T
authors.initials: T
authors.lastname: Lange
authors.forename: S G
authors.initials: SG
authors.lastname: Willis
authors.forename: E P
authors.initials: EP
authors.lastname: Stoffregen
authors.forename: A S
authors.initials: AS
authors.lastname: Corbin
authors.forename: S G
authors.initials: SG
authors.lastname: O'Brien
authors.forename: M C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: B J
authors.initials: BJ
authors.lastname: Druker
authors.forename: P G
authors.initials: PG
authors.lastname: Middleton
authors.forename: M W N
authors.initials: MW
authors.lastname: Deininger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001120:Arginine; D001549:Benzamides; D001782:Blood Donors; D016022:Case-Control Studies; D019008:Drug Resistance, Neoplasm; D005260:Female; D016313:Genes, abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D001120:Arginine