title: BCR-ABL1 kinase domain mutation analysis in an Irish cohort of chronic myeloid leukemia patients.
abstract: While tyrosine kinase inhibitor (TKI) therapy is the mainstay of modern management of chronic myeloid leukemia (CML), a significant proportion of CML patients may be refractory or lose their initial response to TKI therapy through a number of cellular and molecular mechanisms of which acquired mutations in the BCR-ABL1 kinase domain (KD) are the most common. BCR-ABL1 KD mutations were prospectively identified in order to inform clinical decisions on subsequent therapy. Direct sequencing of the BCR-ABL1 KD was performed in 85 CML patients that were either TKI refractory or displayed increasing BCR-ABL1 transcript levels by serial monitoring after an initial molecular response. Twenty-three BCR-ABL1 KD mutations were detected in 21 CML patients and were detected across the KD. Mutations were associated with specific TKI resistance, indicating change and enabling rational selection of subsequent therapy. Serial molecular monitoring of BCR-ABL1 transcripts in CML patients allows appropriate selection of CML patients for BCR-ABL1 KD mutation analysis associated with acquired TKI resistance. Identification of these KD mutations is essential in order to direct alternative treatment strategies in such CML patients.
authors.affiliation: Central Pathology Laboratory, Cancer Molecular Diagnostics, St. James's Hospital, Dublin, Ireland.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: McCarron
authors.forename: Lisa M
authors.initials: LM
authors.lastname: O'Connor
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Langabeer
authors.forename: Eibhlin
authors.initials: E
authors.lastname: Conneally
mesh_terms: D015331:Cohort Studies; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007494:Ireland; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl