Drug Efflux Transporters and Imatinib Mesylate Insensitivity in Chronic Myeloid Leukemia

• Published in: Blood 2012-11, Vol.120 (21), p.4424-4424
• Main Authors: Moreira-Nunes, Caroline Fátima Aquino, Beltrão, Ana Cristina Simões, Francês, Larissa Tatiana Valente Martins, Sousa, Rodrigo Guarischi Mattos Amaral, Silva, Israel Tojal, Silva, Artur Luiz, Silva-Jr, Wilson Araújo, Lemos, José Alexandre Rodrigues
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V120.21.4424.4424

Abstract 4424 Chronic Myeloid Leukemia represents the first human cancer in which a molecular therapy produces an effective clinical response (Holtz Blood 99:3792-800, 2002). The imatinib mesylate (IM) (Novartis Pharmaceuticals™) is a drug, that was designated to inhibit selectively certain tyrosine kinase proteins involved in the process of oncogenesis (Guilhot, The Oncologist, 9:271-81, 2004). In 2005, Michor (Nature 435:1267-70), through mathematical model, concluded that imatinib efficiently reduces the differentiated leukemic cells population, but it has not the same effect on the cell population that drives this disease, the CD34+ leukemic stem cells, which can be kept alive during the treatment. The search for the main causes of imatinib resistance has been intensified in recent years, with a special focus on the possible role of drug transporters (Apperley, Lancet Oncol 8:1018–29, 2007; Baker and Reddy, Mount Sinai J Med, 77:573–86, 2010). These proteins are the main determinants of the intracellular drug concentration, and how they actively regulating the traffic of small molecules through the cell membrane (Melo, Blood 108:1116-7, 2006). Thus, a cell can be resistant to a drug, because the optimum amount of the drug does not stay inside it to a significant effect to be achieved (Kim, Toxicology 182:291-7, 2002). Identify differentially expressed genes in CD34+ and CD66b+ cells as candidates for IM transport. Samples of bone marrow (BM) and peripheral blood (PB) were obtained from five patients with CML treated with imatinib in better then optimal response according to European LeukemiaNet criteria (Baccarani, Blood 108:1809-20, 2006). Cells Isolation and RNA extraction. CD34+ cells were isolated from BM of five patients with CML. Likewise, mature CD66b+ PB cells were isolated from the same patients. SOLiD sequencing and sequence analysis. cDNA was sequenced according to the manufacturer’s protocols for the SOLiD Total RNA-Seq kit for whole transcriptome. Data Analysis. To characterize the class genes, we analyzed the Gene Ontology (GO) annotation (Ashburner, Nature Genetics 25:25-9, 2000), and the software Cufflinks (Trapnell, Nature Biotechnology 28:511–15, 2010) were used to identify the differential expression of genes in both samples, in patients (BM × PB) and in control (BM × PB). The difference in gene expression between compared samples, were calculated based on P < 0.05 significance, were called differentially expressed genes those who su