title: Identification of genes involved in imatinib resistance in CML: a gene-expression profiling approach.
abstract: The use of the tyrosine kinase inhibitor imatinib, which blocks the enzymatic action of the BCR-ABL fusion protein, has represented a critical advance in chronic myeloid leukemia (CML) treatment. However, a subset of patients initially fails to respond to this treatment. Use of complementary DNA (cDNA) microarray expression profiling allows the identification of genes whose expression is associated with imatinib resistance. Thirty-two CML bone marrow samples, collected before imatinib treatment, were hybridized to a cDNA microarray containing 6500 cancer genes, and analyzed using bootstrap statistics. Patients refractory to interferon-alpha treatment were evaluated for cytogenetic and molecular responses for a minimum of 12 months. A set of 46 genes was differentially expressed in imatinib responders and non-responders. This set includes genes involved in cell adhesion (TNC and SCAM-1), drug metabolism (cyclooxygenase 1), protein tyrosine kinases and phosphatases (BTK and PTPN22). A six-gene prediction model was constructed, which was capable of distinguishing cytogenetic response with an accuracy of 80%. This study identifies a set of genes that may be involved in primary resistance to imatinib, suggesting BCR-ABL-independent mechanisms.
authors.affiliation: Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. rvilluendes@cnio.es rvilluendas@cnio.es
authors.forename: R
authors.initials: R
authors.lastname: Villuendas
authors.forename: J L
authors.initials: JL
authors.lastname: Steegmann
authors.forename: M
authors.initials: M
authors.lastname: Pollán
authors.forename: L
authors.initials: L
authors.lastname: Tracey
authors.forename: A
authors.initials: A
authors.lastname: Granda
authors.forename: E
authors.initials: E
authors.lastname: Fernández-Ruiz
authors.forename: L F
authors.initials: LF
authors.lastname: Casado
authors.forename: J
authors.initials: J
authors.lastname: Martínez
authors.forename: P
authors.initials: P
authors.lastname: Martínez
authors.forename: L
authors.initials: L
authors.lastname: Lombardía
authors.forename: L
authors.initials: L
authors.lastname: Villalón
authors.forename: J
authors.initials: J
authors.lastname: Odriozola
authors.forename: M A
authors.initials: MA
authors.lastname: Piris
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001549:Benzamides; D020732:Cytogenetic Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl