Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype

Gréen, Henrik; Falk, Ingrid Jakobsen; Lotfi, Kourosh; Paul, Esbjörn; Hermansson, Monika; Rosenquist, Richard; Paul, Christer; Nahi, Hareth

doi:10.1038/tpj.2010.79

Cited by 40 publications

(39 citation statements)

References 41 publications

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“…According to the literature retrieval strategies and inclusion criteria, seven case-control studies regarding the association between the MDR1 C1236T polymorphism and leukemia risk were included in the present meta-analysis, including 846 leukemia cases and 1,523 controls in total (21)(22)(23)(24)(25)(26)(27). The countries in which these studies were conducted include China, Singapore, Sweden, Brazil and USA.…”

Section: Resultsmentioning

confidence: 99%

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Multidrug resistance gene 1 C1236T polymorphism and susceptibility to leukemia: A meta-analysis

Liu

Ruan

et al. 2014

Biomedical Reports

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Abstract. Several studies have investigated the association between multidrug resistance gene (MDR1) C1236T polymorphism and leukemia risk, however, these published studies have yielded conflicting results. Thus, the present study carried out a meta-analysis to provide a more precise estimate of the effect of this polymorphism on the susceptibility to leukemia. The published case-control studies regarding the association between MDR1 C1236T polymorphism and leukemia risk were included following a computerized search of PubMed, Elsevier, The Cochrane Library, China National Knowledge Infrastructure and Wanfang Database. Either fixed-or random-effects models were applied to calculate the combined odds ratios (ORs) and 95% confidence intervals (CIs) by RevMan 5.2 software. Seven studies, including 846 cases and 1,523 controls, were included in the present meta-analysis. The results indicated that there was no significant association between the MDR1 C1236T polymorphism and leukemia risk in overall comparisons in all four genetic models (CT vs. CC: OR, 1.31, 95% CI, 0.89-1.91, P= 0.17; TT vs. CC: OR, 2.16, 95% CI, 0.99-4.70, P= 0.05; TT vs. CC+CT: OR, 1.72, 95% CI, 0.91-3.25, P= 0.09; and CT+TT vs. CC: OR, 1.57, 95% CI, 0.96-2.56, P= 0.07). In the subgroup analysis according to specific ethnicity, age and the type of leukemia, a significant association was found in adult leukemia (CT+TT vs. CC: OR, 2.77, 95% CI, 1.05-7.31, P=0.04) and chronic myeloid leukemia (CT vs. CC: OR, 1.71, 95% CI, 1.05-2.80, P=0.03). No significant publication bias was detected by funnel plot. Therefore, the meta-analysis indicated that the MDR1 C1236T polymorphism may contribute to the susceptibility to adult leukemia and chronic myeloid leukemia. Furthe well-designed studies based on larger sample sizes are required to validate these findings. IntroductionLeukemia is a malignant clonal disorder of the hematopoietic system with extreme heterogeneity and bad prognosis. In recent years, the incidence of leukemia increased gradually (1), however, the exact biological mechanisms of leukemia have not been fully clarified (2). Epidemiological and case-control studies have found that significant environmental exposures contribute to the pathogenesis of leukemia (3). In addition, previous candidate gene association approaches and genome-wide association studies have identified the presence of inherited genetic susceptibility to this disease (4-7). Therefore, it is generally considered that the causation is multifactorial and that the interaction between exogenous or endogenous exposures and genetic susceptibility plays an important role in the etiology of leukemia (2).The human multidrug resistance gene (MDR1 or ABCB1) locates at 7q21.1 and its cDNA spans ~4.5 kb. MDR1 encodes a 170-kDa membrane transport protein called P-glycoprotein (P-gp), belonging to the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily of transporters (8). P-gp functions as an ATP-dependent efflux pump and is responsible for the efflux of a variety of lipophilic...

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Section: Resultsmentioning

confidence: 99%

“…The countries in which these studies were conducted include China, Singapore, Sweden, Brazil and USA. Among these studies, there were four studies of an Asian population (22,24,25,27), two studies of a Caucasian population (21,23) and one study of a mixed population (26). All the cases had a pathologically confirmed diagnosis of leukemia.…”

Section: Resultsmentioning

confidence: 99%

Multidrug resistance gene 1 C1236T polymorphism and susceptibility to leukemia: A meta-analysis

Liu

Ruan

et al. 2014

Biomedical Reports

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“…Min et al [31] showed that MDR1 G2677T/A gene polymorphisms, as well as haplotypes derived from C1236T, G2677T/A, and C3435T, were associated with individual differences of glucocorticoid treatment in idiopathic thrombocytopenic purpura. Green et al [32] demonstrated that leukemic cells from TT genotype at loci 1236 and 2677 patients were more sensible to mitoxantrone and tended to be more susceptible to etoposide and daunorubicin, for which reason that patients with genotype CC at locus 1236 or GG at locus 2677 showed poorer survival than patients with other genotypes. These results suggest that MDR1 SNPs may have a slight influence on some drug pharmacokinetics and therapeutic response in specific diseases; nevertheless, it seems to be substrate-dependent because different alleles have been associated with different drugs [33].…”

Section: Association Between Mdr1 and Survivalmentioning

confidence: 99%

MDR1 polymorphisms have an impact on the prognosis of Chinese diffuse large B cell lymphoma patients

Yin

Xiao

et al. 2015

Tumor Biol.

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MDR1 (multidrug resistance 1) encodes an adenosine triphosphate (ATP)-dependent efflux transporter that plays a fundamental role in transportation of harmful compounds outside cells to maintain optimal health. The present study was aimed to investigate whether the MDR1 gene single nucleotide polymorphisms (SNPs) were associated with the prognosis of diffuse large B cell lymphoma (DLBCL). Three common SNPs, including C1236T, G2677T/A, and C3435T were focused on, and a total of 150 DLBCL patients from Jiangsu Han population were successively genotyped by polymerase chain reaction-allele-specific primers (PCR-ASP) method or DNA direct sequencing. At locus C1236T, patients carrying T allele (genotype CT and TT) had a prolonged overall survival (OS) when compared with patients with CC genotype (2-year OS 82.6 vs. 60.0 %, respectively; hazard ratio (HR) = 0.1, 95 % confidence interval (CI) 0.01-0.6, p = 0.016). At locus C3435T, complete remission/ complete remission unconfirmed (CR/CRu) rate in C allele group was significantly higher than T allele group (66.7 vs. 51.9 %, respectively; p = 0.009). The progression-free survival (PFS) curves of with T (genotype CT and TT) and without T (genotype CC) were significantly different (2-year PFS 46.4 % in with T group vs. 73.7 % in without T group, respectively; HR = 1.9, 95 % CI 1.0-3.6, p = 0.045). At locus G2677T/A, the age for genotypes AG and AT groups was significantly younger than the other genotypes (51.1 ± 12.6 vs. 57.7 ± 13.4 years, respectively; p = 0.033). In the haplotype analysis of loci 1236-3435, compared with T-C group, the C-T group displayed an inferior PFS rate (2-year PFS 23.0 vs. 50.6 %, respectively; HR = 7.8, 95 % CI 1.9-32.6, p = 0.005), while C-C and T-T groups showed an intermediate PFS rate. Our findings demonstrate that genotype CT + TT at locus C1236T, allele C, and genotype CC at locus C3435T might contribute to a relatively superior prognosis in DLBCL, as well as haplotype of T-C in loci 1236-3435. Besides, genotypes at locus G2677T/A might affect age at diagnosis, which has important prognostic value for DLBCL.

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“…It is well known that differences in P-glycoprotein (encoded by ABCB1) confer different drug resistance patterns to cancer cells. In vitro cytotoxicity studies demonstrated that leukemic cells from patients carrying the polymorphisms 1236T/T and 2677T/T in the ABCB1 gene were significantly more susceptible to MTX than those with other genotypes (Gréen et al 2012). P-glycoprotein is also involved in mitochondrial iron transport (Richardson and Ponka 1997), and therefore, its involvement in the MTX-mediated cardiotoxicity cannot be ruled out (Fig.…”

Section: Ros Generation Iron Accumulation and Mitochondrial Dysfuncmentioning

confidence: 99%

Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone

et al. 2016

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Anthracyclines, e.g., doxorubicin (DOX), and anthracenediones, e.g., mitoxantrone (MTX), are drugs used in the chemotherapy of several cancer types, including solid and non-solid malignancies such as breast cancer, leukemia, lymphomas, and sarcomas. Although they are effective in tumor therapy, treatment with these two drugs may lead to side effects such as arrhythmia and heart failure. At the same clinically equivalent dose, MTX causes slightly reduced cardiotoxicity compared with DOX. These drugs interact with iron to generate reactive oxygen species (ROS), target topoisomerase 2 (Top2), and impair mitochondria. These are some of the mechanisms through which these drugs induce late cardiomyopathy. In this review, we compare the cardiotoxicities of these two chemotherapeutic drugs, DOX and MTX. As described here, even though they share similarities in their modes of toxicant action, DOX and MTX seem to differ in a key aspect. DOX is a more redox-interfering drug, while MTX induces energy imbalance. In addition, DOX toxicity can be explained by underlying mechanisms that include targeting of Top2 beta, mitochondrial impairment, and increases in ROS generation. These modes of action have not yet been demonstrated for MTX, and this knowledge gap needs to be filled.

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Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype

Cited by 40 publications

References 41 publications

Multidrug resistance gene 1 C1236T polymorphism and susceptibility to leukemia: A meta-analysis

Multidrug resistance gene 1 C1236T polymorphism and susceptibility to leukemia: A meta-analysis

MDR1 polymorphisms have an impact on the prognosis of Chinese diffuse large B cell lymphoma patients

Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone

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