MDR1/ABCB1gene polymorphisms in patients with chronic myeloid leukemia

Abstract

BackgroundTyrosine kinase inhibitors (TKIs) are the recommended treatment for patients with chronic myeloid leukemia (CML). The MDR1/ABCB1 gene plays a role in resistance to a wide spectrum of drugs, including TKIs. However, the association of MDR1/ABCB1 gene polymorphisms (SNPs) such as C1236T, G2677T/A, and C3435T with the clinical therapeutic evolution of CML has been poorly studied. We investigated these gene polymorphisms in CML-patients treated with imatinib, nilotinib and/or dasatinib.MethodsABCB1-SNPs were studied in 22 CML-patients in the chronic phase (CP) and 2 CML-patients in blast crisis (BC), all of whom were treated with TKIs, and compared with 25 healthy controls using nested-PCR and sequencing techniques.ResultsSeventeen different haplotypes were identified: 7 only in controls, 6 only in CML-patients, and the remaining 4 in both groups. The distribution ratios of homozygous TT-variants present on each exon between controls and CML-patients were 2.9 for exon 12, and 0.32 for the other 2 exons. Heterozygous T-variants were observed in all controls (100%) and 75% of CML-patients. Wt-haplotype (CC-GG-CC) was observed in 6 CML-patients (25%). In this wt-group, two were treated with nilotinib and reached a major molecular response. The remaining 4 cases had either a minimal or null molecular response, or developed bone marrow aplasia.ConclusionOur results suggest that SNPs of the MDR1/ABCB1 gene could help to characterize the prognosis and the clinical-therapeutic evolution of CML-patients treated with TKIs. Wt-haplotype could be associated with a higher risk of developing CML, and a worse clinical-therapeutic evolution.

Continuous Cytostatic Effects of BCR-ABL Tyrosine Kinase Inhibitors (TKIs) after Washout in Human Leukemic K562 Cells

“…Since previous studies showed that TKIs including imatinib, nilotinib and dasatinib were substrates of MDR-1, the therapeutic effects of TKIs are greatly affected by MDR-1 expression. [13][14][15][16][17] Indeed, our study showed that dasatinib completely suppressed proliferation of parent K562 cells after short-term exposure at a final concentration of 100 ng/mL, but did not suppress proliferation of hMDR-1-transfected cells (Fig. 4D).…”

“…Previous studies have also shown a relationship between therapeutic effect and MDR-1 overexpressions. [13][14][15][16][17] Therefore, it is also necessary to consider the possibility that MDR-1, which is responsible for tolerance of treatment with TKIs, affects maintenance of the therapeutic effect by administration every other day.…”

Haplotypes of ABCB1 1236C >T (rs1128503), 2677G >T/A (rs2032582), and 3435C >T (rs1045642) in patients with bullous pemphigoid

“…A haplotype analysis within ABCB1 performed, i.a., in neoplastic and neurological diseases turned out to be a useful tool in terms of evaluation of the morbidity and the effectiveness of treatment [2, 4, 20, 22, 23, 27, 42, 43, 45]. …”

A study of the association of C3435T polymorphism of MDR1 gene and its mRNA expression with the level of daunorubicin accumulation in leukocytes in patients with chronic myeloproliferative diseases

“…Отсутствие влияния отдельного полиморфизма C3435T (rs1045642) гена MDR1 на риск развития хронических миелопролиферативных заболеваний или развития резистентности к иматинибу в целом согласуется с опубликованными ранее данными о важности одновременной оценки носительства комплекса наиболее информативных однонуклеотидных замен как в гене MDR1, так и в других генах, определяющих распределение и метаболизм ксенобиотиков [3][4][5][6][7][8][9], а также репарацию повреждений ДНК [3].…”

“…Показано также, что слабый полиморфизм C3435T гена MDR1 ассоциирован с более высоким риском развития онкогематологических заболеваний: острых лейкозов [2] и ХМЛ [3,4]. В различных этнических группах было продемонстрировано влияние полиморфизмов MDR1 на развитие резистентности к терапии ХМЛ иматинибом [3][4][5][6][7][8][9]. Было также предложено первичное использование второй линии препаратов, устойчивых к Pgp-эффлюксу, вместо иматиниба у пациентов с полиморфизмами высокого риска резистентности [9].…”