Significance of TPMT and NUDT15 variants in 6-mercaptopurine metabolism in acute lymphoblastic leukaemia/lymphoma patients
https://doi.org/10.35754/0234-5730-2021-66-2-253-262
Abstract
Introduction. Among main curative substances in acute lymphoblastic leukaemia/lymphoma (ALL/LBL) is 6-mercaptopurine (6-MP). However, the severity of adverse reactions (ADRs) to this drug varies considerably among patients, which is sometimes conditioned by individual single nucleotide polymorphisms in key 6-MP metabolism enzyme genes.
Aim — a literature review on the role of TPMT and NUDT15 gene variants in 6-MP metabolism in ALL/LBL.
Main findings. The TPMT and NUDT15 genes encode enzymes mediating key steps of the 6-MP metabolism. The metabolites determine the 6-MP therapeutic and toxic properties, with ADRs emerging when their concentrations alter. A number of TPMT and NUDT15 single nucleotide polymorphisms are associated with varied activities of the encoded enzymes, and their allelic combinations condition functional and non-functional phenotypes. Non-functional variant carriers more likely develop toxicity on 6-MP treatment compared to functional phenotypes. Non-functional TPMT/NUDT15 carriers should have the 6-MP dosage reduced to minimise emerging ADRs.
About the Authors
E. S. Kotova
National Research Center for Hematology
Russian Federation
Russian Federation
Ekaterina S. Kotova, Postgraduate Student, Physician, Department of Intensive High-Dose Chemotherapy for Hemoblastoses and Hematopoietic Depressions
125167, Moscow
O. A. Gavrilina
National Research Center for Hematology
Russian Federation
Russian Federation
Olga A. Gavrilina, Cand. Sci. (Med.), Head of the Observatory Department
125167, Moscow
A. B. Sudarikov
National Research Center for Hematology
Russian Federation
Russian Federation
Andrey B. Sudarikov, Dr. Sci. (Biol.), Head of the Laboratory of Molecular Haematology
125167, Moscow
References
1. Jabbour E., O’Brien S., Konopleva M., Kantarjian H. New insights into the pathophysiology and therapy of adult acute lymphoblastic leukemia. Cancer. 2015; 121(15): 2517–2528. DOI: 10.1002/cncr.29383.
2. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015; 65(1): 5–29. DOI: 10.3322/caac.21254.
3. Moon W., Loftus E.V. Recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2016; 43(8): 863–883. DOI: 10.1111/apt.13559.
4. Nielsen S.N., Grell K., Nersting J., et al. DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): A prospective substudy of a phase 3 trial. Lancet Oncol. 2017; 18(4): 515–524. DOI: 10.1016/S1470-2045(17)30154-7.
5. Kato M., Manabe A. Treatment and biology of pediatric acute lymphoblastic leukemia. Pediatr Int. 2018; 60(1): 4–12. DOI: 10.1111/ped.13457.
6. Elion G.B., Hitchings G.H., Vanderwerff H. Antagonists of nucleic acid derivatives. VI. Purines. J Biol Chem. 1951; 192(2): 505–518.
7. de Boer N.K.H., Peyrin-Biroulet L., Jharap B., et al. Thiopurines in inflammatory bowel disease: New findings and perspectives. J Crohns Colitis. 2018; 12(5): 610–620. DOI: 10.1093/ecco-jcc/jjx181.
8. Sanderson J., Ansari A., Marinaki T., Duley J. Thiopurine methyltransferase: Should it be measured before commencing thiopurine drug therapy? Ann Clin Biochem. 2004; 41(Pt 4): 294–302. DOI: 10.1258/0004563041201455.
9. Sandborn W., Sutherland L., Pearson D., et al. Azathioprine or 6-mercaptopurine for inducing remission of Crohn’s disease. Cochrane database Syst Rev. 2000; (2): CD000545. DOI: 10.1002/14651858.CD000545.
10. Peng X.-X., Shi Z., Damaraju V.L., et al. Up-regulation of MRP4 and down-regulation of influx transporters in human leukemic cells with acquired resistance to 6-mercaptopurine. Leuk Res. 2008; 32(5): 799–809. DOI: 10.1016/j.leukres.2007.09.015.
11. Gray J.H., Owen R.P., Giacomini K.M. The concentrative nucleoside transporter family, SLC28. Pflugers Arch. 2004; 447(5): 728–734. DOI: 10.1007/s00424-003-1107-y.
12. Fotoohi A.K., Wrabel A., Moshfegh A., Albertioni F. Molecular mechanisms underlying the enhanced sensitivity of thiopurine-resistant T-lymphoblastic cell lines to methyl mercaptopurineriboside. Biochem Pharmacol. 2006; 72(7): 816–823. DOI: 10.1016/j.bcp.2006.06.019.
13. Chen Z.S., Lee K., Kruh G.D. Transport of cyclic nucleotides and estradiol 17-beta-D-glucuronide by multidrug resistance protein 4. Resistance to 6-mercaptopurine and 6-thioguanine. J Biol Chem. 2001; 276(36): 33747–33754. DOI: 10.1074/jbc.M104833200.
14. Kakuta Y., Kinouchi Y., Shimosegawa T. Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: Prospects for clinical application of NUDT15 genotyping. J Gastroenterol. 2018; 53: 172–180. DOI: 10.1007/s00535-017-1416-0.
15. Derijks L.J.J., Gilissen L.P.L., Hooymans P.M., Hommes D.W. Review article: thiopurines in inflammatory bowel disease. Aliment Pharmacol Ther. 2006; 24(5): 715–729. DOI: 10.1111/j.1365-2036.2006.02980.x.
16. Brouwer C., De Abreu R.A., Keizer-Garritsen J.J., et al. Thiopurine methyltransferase in acute lymphoblastic leukaemia: Biochemical and molecular biological aspects. Eur J Cancer. 2005; 41(4): 613–623. DOI: 10.1016/j.ejca.2004.10.027.
17. Sparrow M.P., Hande S.A., Friedman S., et al. Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther. 2005; 22(5): 441–446. DOI: 10.1111/j.1365-2036.2005.02583.x
18. Gearry R.B., Barclay M.L., Roberts R.L., et al. Thiopurine methyltransferase and 6-thioguanine nucleotide measurement: Early experience of use in clinical practice. Intern Med J. 2005; 35(10): 580–585. DOI: 10.1111/j.1445-5994.2005.00904.x.
19. Deshpande A.R., Abreu M.T. Optimizing therapy with 6-mercaptopurine and azathioprine: To measure or not to measure? Therap Adv Gastroenterol. 2010; 3(5): 275–279. DOI: 10.1177/1756283X10376121.
20. Tiede I., Fritz G., Strand S., et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest. 2003; 111(8): 1133–1145. DOI: 10.1172/JCI16432.
21. Thomas C.W., Myhre G.M., Tschumper R., et al. Selective inhibition of infl ammatory gene expression in activated T lymphocytes: A mechanism of immune suppression by thiopurines. J Pharmacol Exp Ther. 2005; 312(2): 537–545. DOI: 10.1124/jpet.104.074815.
22. Lennard L., Singleton H.J. High-performance liquid chromatographic assay of the methyl and nucleotide metabolites of 6-mercaptopurine: Quantitation of red blood cell 6-thioguanine nucleotide, 6-thioinosinic acid and 6-methylmercaptopurine metabolites in a single sample. J Chromatogr. 1992; 583(1): 83–90. DOI: 10.1016/0378-4347(92)80347-s.
23. Chrzanowska M., Kolecki P., Duczmal-Cichocka B., Fiet J. Metabolites of mercaptopurine in red blood cells: A relationship between 6-thioguanine nucleotides and 6-methylmercaptopurine metabolite concentrations in children with lymphoblastic leukemia. Eur J Pharm Sci Off J Eur Fed Pharm Sci. 1999; 8(4): 329–334. DOI: 10.1016/s0928-0987(99)00027-5.
24. Lennard L., Lilleyman J.S., Van Loon J., et al. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet. 1990; 336(8709): 225–229. DOI: 10.1016/0140-6736(90)91745-V.
25. Jharap B., Seinen M.L., de Boer N.K.H., et al. Thiopurine therapy in infl ammatory bowel disease patients: analyses of two 8-year intercept cohorts. Inflamm Bowel Dis. 2010;16(9):1541–9. DOI:10.1002/ibd.21221.
26. Moriyama T., Nishii R., Perez-Andreu V., et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016; (48): 367– 373. DOI: 10.1038/ng.3508.
27. Zgheib N.K., Akika R., Mahfouz R., et al. NUDT15 and TPMT genetic polymorphisms are related to 6-mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children’s Cancer Center of Lebanon. Pediatr Blood Cancer. 2017; 64(1): 146–150. DOI: 10.1002/pbc.26189.
28. Weinshilboum R.M., Raymond F.A., Pazmiño P.A. Human erythrocyte thiopurine methyltransferase: Radiochemical microassay and biochemical properties. Clin Chim Acta. 1978; 85(3): 323–333. DOI: 10.1016/0009-8981(78)90311-x.
29. Cara C.J., Pena A.S., Sans M., et al. Reviewing the mechanism of action of thiopurine drugs: Towards a new paradigm in clinical practice. Med Sci Monit Int Med J Exp Clin Res. 2004; 10(11): RA247-54.
30. Colleoni L., Kapetis D., Maggi L., et al. A new thiopurine s-methyltransferase haplotype associated with intolerance to azathioprine. J Clin Pharmacol. 2013; 53(1): 67–74. DOI: 10.1177/0091270011435989.
31. Carvalho A.T.P., Esberard B.C., Fróes R.S.B., et al. Thiopurine-methyltransferase variants in inflammatory bowel disease: Prevalence and toxicity in Brazilian patients. World J Gastroenterol. 2014; 20(12): 3327–3334. DOI: 10.3748/wjg.v20.i12.3327.
32. Gastal G.R., Moreira S., Noble C.F., et al. Toxicity of azathioprine: why and when? analysis of the prevalence of polymorphism in Joinville, SC, Brazil. Arq Gastroenterol. 2012; 49(2): 130–134. DOI: 10.1590/s0004-28032012000200007.
33. Efrati E., Adler L., Krivoy N., Sprecher E. Distribution of TPMT risk alleles for thiopurine [correction of thioupurine] toxicity in the Israeli population. Eur J Clin Pharmacol. 2009; 65(3): 257–262. DOI: 10.1007/s00228-008-0590-7
34. Wang L., Weinshilboum R. Thiopurine S-methyltransferase pharmacogenetics: Insights, challenges and future directions. Oncogene. 2006; (25): 1629– 1638. DOI: 10.1038/sj.onc.1209372.
35. Krynetski E.Y., Schuetz J.D., Galpin A.J., et al. A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. Proc Natl Acad Sci USA. 1995; 92(4) 949–953. DOI: 10.1073/pnas.92.4.949.
36. Armstrong V.W., Shipkova M., von Ahsen N., Oellerich M. Analytic aspects of monitoring therapy with thiopurine medications. Ther Drug Monit. 2004; 26(2): 220–226. DOI: 10.1097/00007691-200404000-00024.
37. Adehin A., Bolaji O.O. Thiopurine S-methyltransferase activity in Nigerians: Phenotypes and activity reference values. BMC Res Notes. 2018; 11(1): 1–5. DOI: 10.1186/s13104-018-3237-5.
38. Coucoutsi C., Emmanouil G., Goulielmos G., et al. Prevalence of thiopurine S-methyltransferase gene polymorphisms in patients with inflammatory bowel disease from the island of Crete, Greece. Eur J Gastroenterol Hepatol. 2017; 29(11): 1284–1289. DOI: 10.1097/MEG.0000000000000947.
39. Yang J.J., Landier W., Yang W., et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol. 2015; 33(11): 1235–1242. DOI: 10.1200/JCO.2014.59.4671.
40. Suarez-Kurtz G., Pena S.D.J. Pharmacogenomics in the Americas: The impact of genetic admixture. Curr Drug Targets. 2006; 7(12): 1649–1658. DOI: 10.2174/138945006779025392.
41. Buaboonnam J., Sripatanatadasakul P., Treesucon A., et al. Effect of NUDT15 on incidence of neutropenia in children with acute lymphoblastic leukemia. Pediatr Int. 2019; 61(8): 754–758. DOI: 10.1111/ped.13905.
42. Carter M., Jemth A.S., Hagenkort A., et al. Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2. Nat Commun. 2015; (6): 7871. DOI: 10.1038/ncomms8871.
43. Valerie N.C.K., Hagenkort A., Page B.D.G., et al. NUDT15 hydrolyzes 6-thio-deoxyGTP to mediate the anticancer efficacy of 6-thioguanine. Cancer Res. 2016; 76(18): 5501–5511. DOI: 10.1158/0008-5472.CAN-16-0584.
44. Liang D.C., Yang C.P., Liu H.C., et al. NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia. Pharmacogenomics J. 2016; 16(6): 536–539. DOI: 10.1038/tpj.2015.75.
45. Chiengthong K., Ittiwut C., Muensri S., et al. NUDT15 c.415C>T increases risk of 6-mercaptopurine induced myelosuppression during maintenance therapy in children with acute lymphoblastic leukemia. Haematologica. 2016; 101(1): e24–e26. DOI: 10.3324/haematol.2015.134775.
46. Tanaka Y., Kato M., Hasegawa D., et al. Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. Br J Haematol. 2015; 171(1): 109–115. DOI: 10.1111/bjh.13518.
47. Suzuki H., Fukushima H., Suzuki R., et al. Genotyping NUDT15 can predict the dose reduction of 6-MP for children with acute lymphoblastic leukemia especially at a preschool age. J Hum Genet. 2016; 61: 797–801. DOI: 10.1038/jhg.2016.55.
48. Soler A.M., Olano N., Méndez Y., et al. TPMT and NUDT15 genes are both related to mercaptopurine intolerance in acute lymphoblastic leukaemia patients from Uruguay. Br J Haematol. 2018: 181(2): 252–255. DOI: 10.1111/bjh.14532.
49. Yi E.S., Choi Y.B., Choi R., et al. NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels in children with acute lymphoblastic leukemia. Cancer Res Treat. 2018; 50(3): 872–882. DOI: 10.4143/crt.2017.283.
50. Shah S.A.V., Paradkar M., Desai D., Ashavaid T. Nucleoside diphosphatelinked moiety X-type motif 15 C415T variant as a predictor for thiopurine-induced toxicity in Indian patients. J Gastroenterol Hepatol. 2017; 32(2): 620–624. DOI: 10.1111/jgh.13494
51. Mezzina N., Campbell Davies S.E., Ardizzone S. Nonbiological therapeutic management of ulcerative colitis. Expert Opin Pharmacother. 2018; 19(16): 1747–1757. DOI: 10.1080/14656566.2018.1525361.
52. Chupova N.V. Genetic polymorphism of thiopurine methyltransferase (TPMT) in children with acute leukemia, residents of the Russian Federation: Dissertation abstract of the candidate of medical sciences. Мoscow, 2004. (In Russian).
53. Relling M.V., Schwab M., Whirl-Carrillo M., et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther. 2019; 105(5): 1095– 1105. DOI: 10.1002/cpt.1304.
54. Schaeffeler E., Fischer C., Brockmeier D., et al. Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-caucasians and identification of novel TPMT variants. Pharmacogenetics. 2004; 14(7): 407–417. DOI: 10.1097/01.fpc.0000114745.08559.db.
55. Kotova E.S., Gavrilina O.A., Yakutik I.A., et al. The role of genetic polymorphisms of TPMT and NUDT15 genes in adult patients with Ph-negative acute lymphoblastic leukemia in Russia. Blood. 2020; 136(Suppl 1): 21–22. DOI: 10.1182/blood-2020-141804.
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For citations:
Kotova E.S., Gavrilina O.A., Sudarikov A.B. Significance of TPMT and NUDT15 variants in 6-mercaptopurine metabolism in acute lymphoblastic leukaemia/lymphoma patients. Russian journal of hematology and transfusiology. 2021;66(2):253-262. (In Russ.) https://doi.org/10.35754/0234-5730-2021-66-2-253-262
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