title: Bcr-Abl expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia.
abstract: Chronic myeloid leukemia (CML) starts with the acquisition of a BCR-ABL fusion gene in a single hematopoietic stem cell, but the time to progression is unpredictable. Although the tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of CML, its continuous administration is associated with development of resistance, particularly in advanced phase or blast crisis. We investigate here whether a feature of disease progression (i.e., elevated expression of Bcr-Abl in CD34+ progenitor cells from CML patients in blast crisis) has any bearing on the kinetics of resistance to imatinib. By studying cell lines that exogenously express Bcr-Abl over the range found from chronic phase to blast crisis of CML, we show that cells expressing high amounts of Bcr-Abl, as in blast crisis, are much less sensitive to imatinib and, more significantly, take a substantially shorter time for yielding a mutant subclone resistant to the inhibitor than cells with low expression levels, as in chronic phase. Our data suggest that the differential levels of the Bcr-Abl oncoprotein expressed by CD34+ CML cells may reflect the extent and duration of their response to imatinib; the relatively high levels of oncoprotein in advanced-phase disease may underlie the observed rapid development of resistance.
authors.affiliation: Department of Haematology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Barnes
authors.forename: Danai
authors.initials: D
authors.lastname: Palaiologou
authors.forename: Eleni
authors.initials: E
authors.lastname: Panousopoulou
authors.forename: Beate
authors.initials: B
authors.lastname: Schultheis
authors.forename: Agnes S M
authors.initials: AS
authors.lastname: Yong
authors.forename: Alice
authors.initials: A
authors.lastname: Wong
authors.forename: Laura
authors.initials: L
authors.lastname: Pattacini
authors.forename: John M
authors.initials: JM
authors.lastname: Goldman
authors.forename: Junia V
authors.initials: JV
authors.lastname: Melo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D001752:Blast Crisis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001549:Benzamides; C082869:CRKL protein; D009687:Nuclear Proteins; D010879:Piperazines; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl