ABCB1 haplotypes are associated with P-gp activity and affect a major molecular response in chronic myeloid leukemia patients treated with a standard dose of imatinib

Abstract

Despite the high efficacy of imatinib mesylate (IM) treatment for chronic myeloid leukemia (CML) patients, some individuals develop resistance due to impaired bioavailability. It has been previously demonstrated that the haplotypes for ATP-binding cassette subfamily B member 1 (ABCB1)with c.1236C>T, c.3435C>T and c.2677G>T/A polymorphisms markedly affect the secondary structure of ABCB1 mRNA and its activity. These modifications may affect efflux transporter activity and response to treatment with IM. The aim of the present study was to investigate the influence of ABCB1 haplotypes on P-glycoprotein (P-gp) activity, IM plasma levels and IM response. In total, 28 chronic-phase CML patients treated with a standard dose of IM (400 mg/day) were studied. The patients were selected according to the haplotypes of ABCB1, with c.1236C>T, c.3435C>T and c.2677G>T polymorphisms, and were classified into two groups based on the presence of the mutated allele in each genotype for the three ABCB1 polymorphisms. In addition, expression of P-gp and breakpoint cluster region-abelson 1 (BCR-ABL1), ABCB1 and solute carrier family 22 member 1 (SLC22A1) mRNA were evaluated. The P-gp activity in the wild-type group was found to be higher than that in the mutated group (59.1 vs. 38.3%; P=0.001). Furthermore, the patients who did not achieve major molecular response (MMR) showed a higher rate of efflux mediated by P-gp when compared with individuals who achieved MMR (64.7 vs. 45.7%; P=0.001). All patients without MMR demonstrated effluxes of >60%. In addition, patients without MMR exhibited lower plasma concentrations of IM compared with those with MMR (0.51 vs. 1.42 μg/ml; P=0.001). Higher levels of SLC22A1 mRNA were observed in patients who achieved MMR and complete molecular response (P<0.05). In conclusion, the ABCB1 1236CT/3435CT/2677GT and 1236TT/3435TT/2677TT haplotypes are associated with reduced P-gp activity and MMR in chronic-phase CML patients treated with a standard dose of IM.

Multidrug resistance gene (MDR1) polymorphisms may not be directly associated with response to imatinib in chronic myeloid leukemia

“…European Leukemia Net defines CMR as BCR-ABL mRNA transcripts undetectable by qRT-PCR and/or nested PCR in two consecutive high-quality samples with sensitivity (Cross et al, 2012). Our results showed that MDR1 rs1128503, rs1045642, and rs2032582 polymorphisms had no significant association with the MMR and CMR in CML patients that received the IM therapy, which is contrary to a few previous studies that showed genetic variations in MDR1 influenced response to IM in CML patients (Seong et al, 2013;Vivona et al, 2014). This might be attributed to the obscure definition of CML and the doses of IM in the included studies.…”

“…SNPs have the potential to affect the expression and function of the P-gp, could also influence the efficiency of absorption or elimination of IM and could explain at least in part variable responses to this drug (Elghannam et al, 2014). Vivona et al (2014) revealed a significant association between MDR1 haplotypes and P-gp activity in CML patients, which further supports our result. This result was also consistent with the result of study reported by B Zu et al (2014), which suggested that MDR1 rs1128503 polymorphism was associated with the increasing risk of IM resistance in Asian CML patients.…”

“…A further screening process excluded studies that were not casecontrol (N = 30), studies not relevant to IM (N = 48), studies unrelated to ABCB1 or MDR1 (N = 41), weakly correlated data in studies (N = 14), insufficient information in studies (N = 16). At the end of the selection process, a total of 10 articles, published between 2008 and 2014, and including 987 patients with CML, were finally selected for meta-analysis (Dulucq et al, 2008;Deenik et al, 2010;Kim et al, 2010;Marin et al, 2010;Takahashi et al, 2010;Ni et al, 2011;Elghannam et al, 2013;Seong et al, 2013;Au et al, 2014;Vivona et al, 2014). Of the 10 studies, 1 was performed in Africans, 4 were performed in Asians, and 5 in Caucasians.…”

“…In IM therapy, IM inhibits BCR-ABL1 from phosphorylating downstream target proteins and blocks the signaling cascade necessary for CML development (Vivona et al, 2014). IM has significantly improved the long-term survival rates and clinical responses in CML patients, but suboptimal responses and treatment failures have also been observed (Jabbour et al, 2009;Seong et al, 2013).…”

“…Although specific genotypes of genes involved in IM bioavailability seem to affect the function of the relative protein, there is still controversy regarding the role of MDR1 genetic variations in the response to IM therapy in patients with CML (Maffioli et al, 2011). While some studies have suggested that MDR1 genetic variations influence response to IM therapy in CML patients (Deenik et al, 2010;Seong et al, 2013;Vivona et al, 2012Vivona et al, , 2014, another study failed to find this correlation (Au et al, 2014). Moreover, few studies have focused on MDR1 and its relation with the clinical features or treatment responses in CML (Vasconcelos et al, 2011).…”