title: Instability of mRNA expression signatures of drug transporters in chronic             myeloid leukemia patients resistant to imatinib.
abstract: Despite the success of imatinib mesylate (IM) in the treatment of chronic             myeloid leukemia (CML), approximately 30% of patients are resistant to therapy,             mostly due to unknown causes. To profile the expression signatures of drug transporters             throughout IM therapy and correlate them with resistance, we quantified mRNA expression             levels of the SLC22A12, ABCB1, ABCC1, ABCG2 and MVP genes in consecutive samples             from peripheral blood or bone marrow of CML patients who were either responsive             or resistant to IM. Additionally we identified and quantified BCR-ABL1 transcript             variants and analyzed 1236T>C ABCB1 and 480G>C SLC22A1 polymorphisms. A             relationship between the type of BCR-ABL1 transcript or ABCB1 or SLC22A1 genotype             and response to treatment was not discovered. However, the studied genes had higher             expression levels in follow-up compared to the diagnostic samples, demonstrating             a possible induction in expression. IM-sensitive patients presented significantly             higher values of SLC22A1 expression, suggesting higher drug influx. Most importantly,             while responding patients demonstrated stable expression signatures in consecutive             samples, there was considerable variation in IM-resistant patients, indicating             that single point sampling expression signatures are not reliable in predicting             clinical outcomes or prognostic features in these patients. Studies that assessed             consecutive samples from CML patients in order to evaluate the variation in expression             levels of transporter genes are limited yet our study emphasizes the importance             of such approaches.
authors.affiliation: Human Molecular Genetics Research Centre, Department of Genetics, New University of Lisbon, Lisbon, Portugal. marta.gromicho@fcm.unl.pt
authors.forename: Marta
authors.initials: M
authors.lastname: Gromicho
authors.forename: Marta
authors.initials: M
authors.lastname: Magalhães
authors.forename: Fátima
authors.initials: F
authors.lastname: Torres
authors.forename: Joana
authors.initials: J
authors.lastname: Dinis
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Fernandes
authors.forename: Paula
authors.initials: P
authors.lastname: Rendeiro
authors.forename: Purificação
authors.initials: P
authors.lastname: Tavares
authors.forename: António
authors.initials: A
authors.lastname: Laires
authors.forename: José
authors.initials: J
authors.lastname: Rueff
authors.forename: António
authors.initials: A
authors.lastname: Sebastião Rodrigues
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism*; D018709:Statistics, Nonparametric; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics; D055815:Young Adult; D000099187:Major Vault Protein
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001549:Benzamides; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C581634:BCR-ABL1 fusion protein, human; C491241:SLC22A12 protein, human; C421109:multidrug resistance-associated protein 1