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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Reduced ABCG2 and increased SLC22A1 mRNA expression are associated with imatinib response in chronic myeloid leukemia

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de Lima, Luciene Terezina [1] ; Vivona, Douglas [1] ; Bueno, Carolina Tosin [1] ; Hirata, Rosario D. C. [1] ; Hirata, Mario H. [1] ; Luchessi, Andre D. [1] ; de Castro, Fabiola Attie [2] ; Chauffaille, Maria de Lourdes F. [3] ; Zanichelli, Maria A. [4] ; Chiattone, Carlos S. [5] ; Hungria, Vania T. M. [5] ; Guerra-Shinohara, Elvira M. [1]
Total Authors: 12
Affiliation:
[1] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, BR-05508000 Sao Paulo - Brazil
[2] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Toxicol & Bromatol Anal, BR-14049 Ribeirao Preto - Brazil
[3] Univ Fed Sao Paulo, Dept Hematol, Sao Paulo - Brazil
[4] Hosp Brigadeiro, Dept Hematol, Sao Paulo - Brazil
[5] Santa Casa de Misericordia Sao Paulo, Fac Med Sci, Discipline Hematol & Oncol, Sao Paulo - Brazil
Total Affiliations: 5
Document type: Journal article
Source: MEDICAL ONCOLOGY; v. 31, n. 3 MAR 2014.
Web of Science Citations: 16
Abstract

Imatinib mesylate (IM) has become a standard of care in chronic myeloid leukemia (CML) therapy. Single nucleotide polymorphisms (SNPs) and altered expression in drug transporter genes may influence IMresponse. In order to investigate whether mRNA expression and SNPs in drug transporters are associated with IM resistance, we studied 118 chronic-phase CML patients receiving the standard dose of IM (400 mg/day). They were assigned as responders and non-responders according to European Leukemia Net criteria (2009). mRNA expression in samples at diagnosis (without IM therapy) and outcomes after IM failure were also evaluated in subgroups of patients. Major molecular response (MMR), complete molecular response and primary and secondary resistance were all assessed. BCR-ABL1, ABCB1, ABCG2, SLC22A1 and SLCO1A2 mRNA expression and SNPs in ABCG2 and SLC22A1 genes were analyzed. ABCG2 mRNA expression in the non-responders was higher before and during IM therapy. Furthermore, ABCG2 was overexpressed in those who did not achieve MMR (P = 0.027). In a subgroup of patients who switched to second-generation tyrosine kinase inhibitors, high mRNA expression of ABCG2 was associated with a risk of 24 times that of not achieving complete cytogenetic response (OR 24.00, 95 % CI 1.74-330.80; P = 0.018). In the responder group, patients who achieved MMR (P = 0.009) presented higher mRNA levels of SLC22A1. The SNPs were not associated with mRNA expression of ABCG2 and SLC22A1. Our data suggest that elevated ABCG2 expression (an efflux transporter) could be associated with IM resistance and could impact on second-generation TKI response, whereas high SLC22A1 expression (an influx transporter) may be associated with a successful IM therapy in CML patients. (AU)