title: BCR-ABL isoforms associated with intrinsic or acquired resistance to imatinib: more heterogeneous than just ABL kinase domain point mutations?
abstract: Imatinib, a small molecule inhibitor of ABL, PDGFR and C-KIT, has revolutionized treatment of chronic myeloid leukaemia (CML). However, resistance to treatment is of increasing importance and often is due to point mutations in the Abl kinase domain (Abl KD). Here, we analysed clinical outcome and mutation status in two independent Nordic populations (n = 77) of imatinib-resistant CML patients. We detected BCR-ABL transcripts containing point mutations of residues in the P-loop, A-loop and other kinase domain residues in 32 patients (42%). In contrast to previous data, mutations in BCR-ABL were as frequently found in patients with primary resistance (56%) as with secondary resistance (53%). No T315I mutations were found in the study cohort. BCR-ABL splice variants were identified in a significant number of our cases (19%): BCR-ABL transcripts of variable length; a variant fusion transcript joining BCR exon 14 sequences to ABL exon 4; partial, in-frame-deletion of exon 4 due to induction of a cryptic splice site by the L248V and finally, alternative splicing of ABL exon 7 sequences. Though the majority of splice variants observed in this study do not encode functional proteins, alternative splicing appears to represent a common phenomenon in the biology of CML. We conclude that Abl KD point mutations represent a major mechanism of imatinib resistance. Other sequence irregularities were also detected, but their significance in conferring resistance is unclear. Diagnostic strategies looking for imatinib-resistant clones should be designed to detect a broader profile of BCR-ABL variants than just point mutations.
authors.affiliation: Department of Pharmacology, Institute of Pharmacy, University of Tromsø, Tromsø, Norway. franz.gruber@uit.no
authors.forename: Franz X
authors.initials: FX
authors.lastname: Gruber
authors.forename: Tuija
authors.initials: T
authors.lastname: Lundán
authors.forename: Rasmus
authors.initials: R
authors.lastname: Goll
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Silye
authors.forename: Ingvild
authors.initials: I
authors.lastname: Mikkola
authors.forename: Ole Petter
authors.initials: OP
authors.lastname: Rekvig
authors.forename: Sakari
authors.initials: S
authors.lastname: Knuutila
authors.forename: Kari
authors.initials: K
authors.lastname: Remes
authors.forename: Tobias
authors.initials: T
authors.lastname: Gedde-Dahl
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.forename: Henrik
authors.initials: H
authors.lastname: Hjorth-Hansen
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-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 / Q000627:therapeutic use; D017354:Point Mutation; D020033:Protein Isoforms / Q000235:genetics; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D020033:Protein Isoforms; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl