RNA Expression and Polymorphisms in Imatinib Influx and Efflux Transporters Influence Molecular Response to Imatinib Therapy in Newly Diagnosed Patients with Chronic Myeloid Leukemia

• Published in: Blood 2012-11, Vol.120 (21), p.2785-2785
• Main Authors: Balasubramanian, Poonkuzhali, Markose, Preetha, Anandhan, Senthamizh Selvi, Sahu, Ramkrishna, Kumaraswamy, Vinodhini, Srivastava, Vivi, Ahmed, Rayaz, Abraham, Aby, George, Biju, Chandy, Mammen, Srivastava, Alok, Mathews, Vikram
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V120.21.2785.2785

Abstract 2785 Targeted therapy in CML with tyrosine kinase inhibitor (TKI) imatinib has resulted in significant improvement in outcome. However, resistance and intolerance to imatinib have seriously limited the success of this therapy, with only a proportion of patients achieving major molecular response (MMR). It is important to identify predictors of response to imatinib, since early switch to second generation TKI has been shown to improve outcome in non-responders. Overexpression of efflux transporters, decreased expression of influx transporters and polymorphisms in these transporters and drug metabolizing enzymes have been shown to influence imatinib therapy. We evaluated the role of RNA expression and polymorphisms in imatinib influx and efflux transporters in 86 newly diagnosed patients with CML at our centre receiving imatinib from December 2009 till April 2012. Total RNA was extracted and RNA expression of the transporter genes ABCA3 (sequesters imatinib; increased expression shown to decrease imatinib exposure), ABCB1, ABCG2 (both efflux transporters) and SLC22A1 (influx transporter) were analyzed with GAPDH as housekeeping gene using Taqman based gene expression assays. The dCT values (where dCT = CT value of target gene – CT value of housekeeping gene; lower dCT corresponds to higher expression and vice versa) were used for comparing expression between groups. Polymorphisms in ABCB1 (T1236C, T2677A, and C3435T), ABCG2 (Ex2 G34A and Ex5 C421A, promoter SNP -15994C->T), SLC22A1 (all coding exons) that were associated with the expression of these transporters were analyzed from genomic DNA samples by PCR followed by direct sequencing or RFLP. BCR-ABL transcript levels were monitored at diagnosis, 3, 6, 9, 12, 18, 24 and 30 months after start of imatinib. Molecular response to imatinib after a minimum of 12 months was calculated using the ratio of BCR-ABL to ABL transcript expressed in International scale. Patients were classified to have MMR (BCR-ABL/ABL 0.01; but complete or partial cytogenetic response [CCR or PCR] based on FISH analysis at around 12 months from the start of imatinib therapy), and resistant (BCR-ABL/ABL >10; no cytogenetic response even after imatinib dose was increased), or intolerant (severe cytopenia or skin toxicity requiring frequent dose reductions). The RNA expression was compared between different groups by ANOVA and the effect of SNPs on outcome was compared by Fisher’s test. Out of the 8