Polymorphism in multidrug resistance-associated protein gene 3 is associated with outcomes in childhood acute lymphoblastic leukemia

ABSTRACT Multidrug resistance-related proteins (MRPs) 2, 3 and 5 are involved in the efflux of drugs used in acute lymphoblastic leukemia (ALL) treatment. Polymorphisms of these genes were

investigated for an association with treatment responses in 273 childhood ALL patients. The _MRP3_ A−189 allele of the regulatory AT polymorphism was associated with reduced event-free

survival (_P_=0.01). The results remained significant after adjustment for multiple comparisons and in the multivariate analysis. Among patients with an event, the A−189 carriers had

significantly higher methotrexate plasma levels (_P_=0.03). _MRP3_ A−189 also conferred four times higher risk of a relapse in central nervous system (_P_=0.01). Patients with this allele

tended to have lower frequency of thrombocytopenia grade 2 (_P_=0.06). Gene reporter assay showed that the haplotype tagged by the A−189 had higher promoter activity (_P_⩽0.01). In

conclusion, _MRP3_ A−189 T polymorphism was associated with treatment responses in ALL, likely due to the change in MRP3 efflux. Access through your institution Buy or subscribe This is a

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RS460089 IN THE GENE PROMOTER OF THE DRUG TRANSPORTER OCTN1 HAS PROGNOSTIC VALUE FOR TREATMENT-FREE REMISSION IN CHRONIC MYELOID LEUKEMIA PATIENTS TREATED WITH IMATINIB Article Open access

21 December 2023 THE ACQUISITION ORDER OF LEUKEMIC DRUG RESISTANCE MUTATIONS IS DIRECTED BY THE SELECTIVE FITNESS ASSOCIATED WITH EACH RESISTANCE MECHANISM Article Open access 11 August 2023

ASSOCIATION OF _ITPA_ GENE POLYMORPHISMS WITH ADVERSE EFFECTS OF AZA/6-MP ADMINISTRATION: A SYSTEMATIC REVIEW AND META-ANALYSIS Article 17 January 2022 REFERENCES * Ansari M, Krajinovic M .

Pharmacogenomics in cancer treatment defining genetic bases for inter-individual differences in responses to chemotherapy. _Curr Opin Pediatr_ 2007; 19: 15–22. Article  PubMed  Google

Scholar  * Cheok MH, Evans WE . Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy. _Nat Rev Cancer_ 2006; 6: 117–129. Article  CAS  PubMed  Google Scholar  *

Pui CH, Howard SC . Current management and challenges of malignant disease in the CNS in paediatric leukaemia. _Lancet Oncol_ 2008; 9: 257–268. Article  PubMed  Google Scholar  * Ansari M,

St-Onge G, Krajinovic M . [Pharmacogenomics of acute lymphoblastic leukemia]. _Med Sci (Paris)_ 2007; 23: 961–967. Article  Google Scholar  * Assaraf YG . The role of multidrug resistance

efflux transporters in antifolate resistance and folate homeostasis. _Drug Resist Updat_ 2006; 9: 227–246. Article  CAS  PubMed  Google Scholar  * Kock K, Grube M, Jedlitschky G, Oevermann

L, Siegmund W, Ritter CA _et al_. Expression of adenosine triphosphate-binding cassette (ABC) drug transporters in peripheral blood cells: relevance for physiology and pharmacotherapy. _Clin

Pharmacokinet_ 2007; 46: 449–470. Article  PubMed  Google Scholar  * Cascorbi I . Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. _Pharmacol

Ther_ 2006; 112: 457–473. Article  CAS  PubMed  Google Scholar  * Conseil G, Deeley RG, Cole SP . Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters. _Pharmacogenet

Genomics_ 2005; 15: 523–533. Article  CAS  PubMed  Google Scholar  * Assaraf YG . Molecular basis of antifolate resistance. _Cancer Metastasis Rev_ 2007; 26: 153–181. Article  CAS  PubMed 

Google Scholar  * Hooijberg JH, Broxterman HJ, Kool M, Assaraf YG, Peters GJ, Noordhuis P _et al_. Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. _Cancer

Res_ 1999; 59: 2532–2535. CAS  Google Scholar  * Wielinga P, Hooijberg JH, Gunnarsdottir S, Kathmann I, Reid G, Zelcer N _et al_. The human multidrug resistance protein MRP5 transports

folates and can mediate cellular resistance against antifolates. _Cancer Res_ 2005; 65: 4425–4430. Article  CAS  PubMed  Google Scholar  * Kool M, van der Linden M, de Haas M, Scheffer GL,

de Vree JM, Smith AJ _et al_. MRP3, an organic anion transporter able to transport anti-cancer drugs. _Proc Natl Acad Sci USA_ 1999; 96: 6914–6919. Article  CAS  PubMed  Google Scholar  *

Zeng H, Chen ZS, Belinsky MG, Rea PA, Kruh GD . Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport.

_Cancer Res_ 2001; 61: 7225–7232. CAS  PubMed  Google Scholar  * Assaraf YG, Rothem L, Hooijberg JH, Stark M, Ifergan I, Kathmann I _et al_. Loss of multidrug resistance protein 1 expression

and folate efflux activity results in a highly concentrative folate transport in human leukemia cells. _J Biol Chem_ 2003; 278: 6680–6686. Article  CAS  PubMed  Google Scholar  * Gradhand

U, Kim RB . Pharmacogenomics of MRP transporters (ABCC1-5) and BCRP (ABCG2). _Drug Metabolism Rev_ 2008; 40: 317–354. Article  CAS  Google Scholar  * Ansari M, Sauty G, Labuda M, Gagne V,

Laverdiere C, Moghrabi A _et al_. Polymorphisms in multidrug ressistance-associated protein Gene 4 is Associated with outcome childhood acute lymphoblastic leukemia. _Blood_ 2009; 114:

1383–1386. Article  CAS  PubMed  Google Scholar  * Moghrabi A, Levy DE, Asselin B, Barr R, Clavell L, Hurwitz C _et al_. Results of the Dana-Farber cancer institute ALL consortium protocol

95-01 for children with acute lymphoblastic leukemia. _Blood_ 2007; 109: 896–904. Article  CAS  PubMed  PubMed Central  Google Scholar  * Silverman LB, Declerck L, Gelber RD, Dalton VK,

Asselin BL, Barr RD _et al_. Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981–1995). _Leukemia_ 2000; 14:

2247–2256. Article  CAS  PubMed  Google Scholar  * Silverman LB, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell LA _et al_. Improved outcome for children with acute lymphoblastic

leukemia: results of Dana-Farber Consortium Protocol 91-01. _Blood_ 2001; 97: 1211–1218. Article  CAS  PubMed  Google Scholar  * Silverman LB, Stevenson KE, O’Brien JE, Asselin BL, Barr RD,

Clavell L _et al_. Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985–2000). _Leukemia_ 2010; 24:

320–334. Article  CAS  PubMed  Google Scholar  * Costea I, Moghrabi A, Laverdiere C, Graziani A, Krajinovic M . Folate cycle gene variants and chemotherapy toxicity in pediatric patients

with acute lymphoblastic leukemia. _Haematologica_ 2006; 91: 1113–1116. CAS  PubMed  Google Scholar  * Bourgeois S, Labuda D . Dynamic allele-specific oligonucleotide hybridization on solid

support. _Anal Biochem_ 2004; 324: 309–311. Article  CAS  PubMed  Google Scholar  * Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population

data. _Am J Human Genet_ 2001; 68: 978–989. Article  CAS  Google Scholar  * Storey JD, Taylor JE, Siegmund D . Strong control, conservative point estimation, and simultaneous conservative

consistency of false discovery rates: a unified approach. _J R Stat Soc Ser B_ 2004; 66: 187–205. Article  Google Scholar  * Takada T, Suzuki H, Sugiyama Y . Characterization of 5′-flanking

region of human MRP3. _Biochem Biophys Res Commun_ 2000; 270: 728–732. Article  CAS  PubMed  Google Scholar  * Dulucq S, St-Onge G, Gagne V, Ansari M, Sinnett D, Labuda D _et al_. DNA

variants in the dihydrofolate reductase gene and outcome in childhood ALL. _Blood_ 2008; 111: 3692–3700. Article  CAS  PubMed  Google Scholar  * Steinbach D, Wittig S, Cario G, Viehmann S,

Mueller A, Gruhn B _et al_ The multidrug resistance-associated protein 3 (MRP3) is associated with a poor outcome in childhood ALL and may account for the worse prognosis in male patients

and T-cell immunophenotype. _Blood_ 2003; 102: 4493–4498. Article  CAS  PubMed  Google Scholar  * Steinbach D, Lengemann J, Voigt A, Hermann J, Zintl F, Sauerbrey A . Response to

chemotherapy and expression of the genes encoding the multidrug resistance-associated proteins MRP2, MRP3, MRP4, MRP5, and SMRP in childhood acute myeloid leukemia. _Clin Cancer Res_ 2003;

9: 1083–1086. CAS  PubMed  Google Scholar  * Kitamura Y, Hirouchi M, Kusuhara H, Schuetz JD, Sugiyama Y . Increasing systemic exposure of methotrexate by active efflux mediated by multidrug

resistance-associated protein 3 (mrp3/abcc3). _J Pharmacol Exp Ther_ 2008; 327: 465–473. Article  CAS  PubMed  Google Scholar  * Kobayashi K, Ito K, Takada T, Sugiyama Y, Suzuki H .

Functional analysis of nonsynonymous single nucleotide polymorphism type ATP-binding cassette transmembrane transporter subfamily C member 3. _Pharmacogenet Genomics_ 2008; 18: 823–833.

Article  CAS  PubMed  Google Scholar  * Lang T, Hitzl M, Burk O, Mornhinweg E, Keil A, Kerb R _et al_. Genetic polymorphisms in the multidrug resistance-associated protein 3 (ABCC3, MRP3)

gene and relationship to its mRNA and protein expression in human liver. _Pharmacogenetics_ 2004; 14: 155–164. Article  CAS  PubMed  Google Scholar  * Muller P, Asher N, Heled M, Cohen SB,

Risch A, Rund D . Polymorphisms in transporter and phase II metabolism genes as potential modifiers of the predisposition to and treatment outcome of _de novo_ acute myeloid leukemia in

Israeli ethnic groups. _Leukemia Res_ 2008; 32: 919–929. Article  Google Scholar  * Muller PJ, Dally H, Klappenecker CN, Edler L, Jager B, Gerst M _et al_. Polymorphisms in ABCG2, ABCC3 and

CNT1 genes and their possible impact on chemotherapy outcome of lung cancer patients. _Int J Cancer_ 2009; 124: 1669–1674. Article  PubMed  Google Scholar  * Gradhand U, Tegude H, Burk O,

Eichelbaum M, Fromm MF, Konig J . Functional analysis of the polymorphism -211C>T in the regulatory region of the human ABCC3 gene. _Life Sci_ 2007; 80: 1490–1494. Article  CAS 

PubMed  Google Scholar  * Doerfel C, Rump A, Sauerbrey A, Gruhn B, Zintl F, Steinbach D . In acute leukemia, the polymorphism -211C>T in the promoter region of the multidrug

resistance-associated protein 3 (MRP3) does not determine the expression level of the gene. _Pharmacogenet Genomics_ 2006; 16: 149–150. Article  CAS  PubMed  Google Scholar  * Begley DJ .

ABC transporters and the blood-brain barrier. _Curr Pharm Des_ 2004; 10: 1295–1312. Article  CAS  PubMed  Google Scholar  * Valera ET, Lucio-Eterovic AK, Neder L, Scrideli CA, Machado HR,

Carlotti-Junior CG _et al_. Quantitative PCR analysis of the expression profile of genes related to multiple drug resistance in tumors of the central nervous system. _J Neurooncol_ 2007; 85:

1–10. Article  CAS  PubMed  Google Scholar  * Bronger H, Konig J, Kopplow K, Steiner HH, Ahmadi R, Herold-Mende C _et al_. ABCC drug efflux pumps and organic anion uptake transporters in

human gliomas and the blood-tumor barrier. _Cancer Res_ 2005; 65: 11419–11428. Article  CAS  PubMed  Google Scholar  * Nies AT, Jedlitschky G, Konig J, Herold-Mende C, Steiner HH, Schmitt HP

_et al_. Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain. _Neuroscience_ 2004; 129: 349–360. Article  CAS  PubMed  Google

Scholar  * Dauchy S, Dutheil F, Weaver RJ, Chassoux F, Daumas-Duport C, Couraud PO _et al_. ABC transporters, cytochromes P450 and their main transcription factors: expression at the human

blood-brain barrier. _J Neurochem_ 2008; 107: 1518–1528. Article  CAS  PubMed  Google Scholar  * Berezowski V, Landry C, Dehouck MP, Cecchelli R, Fenart L . Contribution of glial cells and

pericytes to the mRNA profiles of P-glycoprotein and multidrug resistance-associated proteins in an _in vitro_ model of the blood-brain barrier. _Brain Res_ 2004; 1018: 1–9. Article  CAS 

PubMed  Google Scholar  * Warren MS, Zerangue N, Woodford K, Roberts LM, Tate EH, Feng B _et al_. Comparative gene expression profiles of ABC transporters in brain microvessel endothelial

cells and brain in five species including human. _Pharmacol Res_ 2009; 59: 404–413. Article  CAS  PubMed  Google Scholar  * Haenisch S, Zimmermann U, Dazert E, Wruck CJ, Dazert P, Siegmund W

_et al_. Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex. _Pharmacogenomics J_ 2007; 7: 56–65. Article  CAS  PubMed 

Google Scholar  * Laechelt S, Turrini E, Ruehmkorf A, Siegmund W, Cascorbi I, Haenisch S . Impact of ABCC2 haplotypes on transcriptional and posttranscriptional gene regulation and function.

_Pharmacogenomics J_ 2011; 11: 25–34. Article  CAS  PubMed  Google Scholar  * Naesens M, Kuypers DR, Verbeke K, Vanrenterghem Y . Multidrug resistance protein 2 genetic polymorphisms

influence mycophenolic acid exposure in renal allograft recipients. _Transplantation_ 2006; 82: 1074–1084. Article  CAS  PubMed  Google Scholar  * Han JY, Lim HS, Yoo YK, Shin ES, Park YH,

Lee SY _et al_. Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer. _Cancer_

2007; 110: 138–147. Article  PubMed  Google Scholar  * Choi JH, Ahn BM, Yi J, Lee JH, Nam SW, Chon CY _et al_. MRP2 haplotypes confer differential susceptibility to toxic liver injury.

_Pharmacogenet Genomics_ 2007; 17: 403–415. Article  CAS  PubMed  Google Scholar  * Rau T, Erney B, Gores R, Eschenhagen T, Beck J, Langer T . High-dose methotrexate in pediatric acute

lymphoblastic leukemia: impact of ABCC2 polymorphisms on plasma concentrations. _Clin Pharmacol Ther_ 2006; 80: 468–476. Article  CAS  PubMed  Google Scholar  * Haenisch S, May K, Wegner D,

Caliebe A, Cascorbi I, Siegmund W . Influence of genetic polymorphisms on intestinal expression and rifampicin-type induction of ABCC2 and on bioavailability of talinolol. _Pharmacogenet

Genomics_ 2008; 18: 357–365. Article  CAS  PubMed  Google Scholar  * Ranganathan P, Culverhouse R, Marsh S, Mody A, Scott-Horton TJ, Brasington R _et al_. Methotrexate (MTX) pathway gene

polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis. _J Rheumatol_ 2008; 35: 572–579. CAS  PubMed  Google Scholar  * Niemi M,

Arnold KA, Backman JT, Pasanen MK, Godtel-Armbrust U, Wojnowski L _et al_. Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance-associated protein 2 expression and

pravastatin pharmacokinetics. _Pharmacogenet Genomics_ 2006; 16: 801–808. Article  CAS  PubMed  Google Scholar  * Wojnowski L, Kulle B, Schirmer M, Schluter G, Schmidt A, Rosenberger A _et

al_. NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. _Circulation_ 2005; 112: 3754–3762. Article  CAS  Google

Scholar  * Leschziner G, Zabaneh D, Pirmohamed M, Owen A, Rogers J, Coffey AJ _et al_. Exon sequencing and high resolution haplotype analysis of ABC transporter genes implicated in drug

resistance. _Pharmacogenet Genomics_ 2006; 16: 439–450. Article  CAS  PubMed  Google Scholar  * Dazert P, Meissner K, Vogelgesang S, Heydrich B, Eckel L, Bohm M _et al_. Expression and

localization of the multidrug resistance protein 5 (MRP5/ABCC5), a cellular export pump for cyclic nucleotides, in human heart. _Am J Pathol_ 2003; 163: 1567–1577. Article  CAS  PubMed 

PubMed Central  Google Scholar  * Stojic J, Stohr H, Weber BH . Three novel ABCC5 splice variants in human retina and their role as regulators of ABCC5 gene expression. _BMC Mol Biol_ 2007;

8: 42. Article  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS We are thankful to all patients and their parents who consented to participate in genetics study

related to leukemia. This work was supported by grants from the Leukaemia Lymphoma Society of Canada, CIHR, Research Centre of CHU Sainte-Justine, Charles Bruneau Foundation and Centre

d’Excellence en Oncologie Pédiatrique et en Soins Palliatifs. MK and DS are scholars of the Fonds de la Recherche en Santé du Québec, MA is scholar of the Swiss National Fund, Charles

Bruneau and Telemaque foundations. Gene reporter assay was carried out in part within the project of Genome Quebec/Genome Canada: gene regulators in disease. _Author contributions:_ MA, GS,

ML, JR, VG performed experiments, MA, AM, CL contributed to the retrieval of clinical data; MA, VG and MK performed the analysis; MK designed the research; DS contributed in part to the gene

reporter assay; MA and MK drafted the article; all authors contributed to the interpretation of data and revised the paper critically. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Research

Center, CHU Sainte-Justine, Montreal, Quebec, Canada M Ansari, G Sauty, M Labuda, V Gagné, J Rousseau, A Moghrabi, C Laverdière, D Sinnett & M Krajinovic * Department of Pediatrics,

University Hospital of Geneva, Geneva, Switzerland M Ansari * Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada A Moghrabi, C Laverdière, D Sinnett & M

Krajinovic * Department of Pharmacology, University of Montreal, Montreal, Quebec, Canada M Krajinovic Authors * M Ansari View author publications You can also search for this author

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search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to M Krajinovic. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest.

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Ansari, M., Sauty, G., Labuda, M. _et al._ Polymorphism in multidrug resistance-associated protein gene 3 is associated with outcomes in childhood acute lymphoblastic leukemia.

_Pharmacogenomics J_ 12, 386–394 (2012). https://doi.org/10.1038/tpj.2011.17 Download citation * Received: 28 July 2010 * Revised: 16 March 2011 * Accepted: 18 April 2011 * Published: 24 May

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Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * multidrug

resistance-associated proteins * polymorphisms * pharmacogenetics * childhood leukemia * treatment * outcomes