Volume 14, Issue 2 ( June 2022 2022)                   Iranian Journal of Blood and Cancer 2022, 14(2): 75-84 | Back to browse issues page

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Siyadat P, Yazdandoust E, Sheikhi M, Ayatollahi H. NUDT15 genetic variants and 6-mercaptopurine intolerance in pediatric acute lymphoblastic leukemia: an updated review. Iranian Journal of Blood and Cancer 2022; 14 (2) :75-84
URL: http://ijbc.ir/article-1-1109-en.html
NUDT15 genetic variants and 6-mercaptopurine intolerance in pediatric acute lymphoblastic leukemia: an updated review
Payam Siyadat1 , Ehsan Yazdandoust2 , Maryam Sheikhi3 , Hossein Ayatollahi * 4
1- Department of Hematology, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
2- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
3- Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
4- Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran , ayatollahihossein@yahoo.com
Abstract:   (1167 Views)
Acute lymphoblastic leukemia (ALL) accounts for nearly 30% of pediatric cancers. The maintenance treatment for ALL comprises daily oral 6-mercaptopurine (6-MP) and weekly methotrexate (MTX). 6-MP is a purine analog that can significantly improve the long-term survival of ALL patients. Despite more than 90% of 5-year survival of childhood ALL in developed countries, treatment interruption due to drug toxicities continues to be a grave concern during therapy. Several studies have highlighted the association between some genetic variants and 6-MP toxicities in ALL patients. Some variants of 6-MP metabolizing enzymes received much attention as possible predictors of myelotoxicity following 6-MP therapy. Recently, two landmark genome-wide association studies have highlighted variants in nucleoside diphosphate–linked moiety X-type motif 15 (NUDT15) as promising indicators of 6-MP toxicities. It seems that NUDT15 genotyping can help determine the optimum dose of 6-MP and prevent toxicities, especially fatal myelotoxicity. No association was found between NUDT15 variants and hepatotoxicity or survival rates of ALL patients in previous studies. However, further studies are warranted to shed more light on these issues. The current review updates and evaluates the available scientific data regarding different genetic variants of NUDT15 and their possible roles in 6-MP intolerance in various ethnic groups.
Keywords: 6-Mercaptopurine, NUDT15, Leukopenia, polymorphism, pediatric, acute lymphoblastic leukemia
Full-Text [PDF 876 kb]   (743 Downloads)    
: Review Article | Subject: Pediatric Hematology & Oncology
Received: 2021/01/15 | Accepted: 2022/06/4 | Published: 2022/06/28
References
1. Karol, S.E. and C.-H. Pui, Personalized therapy in pediatric high-risk B-cell acute lymphoblastic leukemia. Therapeutic Advances in Hematology, 2020. 11: p. 2040620720927575. [DOI:10.1177/2040620720927575]
2. Vijayakrishnan, J., et al., Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk. Nature communications, 2019. 10(1): p. 1-9. [DOI:10.1038/s41467-019-13069-6]
3. Greaves, M., A causal mechanism for childhood acute lymphoblastic leukaemia. Nature Reviews Cancer, 2018. 18(8): p. 471-484. https://doi.org/10.1038/s41568-018-0015-6 [DOI:10.1038/s41568-018-0029-0]
4. Tran, T.H. and S.P. Hunger. The Genomic Landscape of Pediatric Acute Lymphoblastic Leukemia and Precision Medicine Opportunities. in Seminars in Cancer Biology. 2020. Elsevier.
5. Chiarini, F., et al., Advances in understanding the acute lymphoblastic leukemia bone marrow microenvironment: From biology to therapeutic targeting. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 2016. 1863(3): p. 449-463. [DOI:10.1016/j.bbamcr.2015.08.015]
6. Siyadat, P., et al., High Resolution Melting Analysis for Evaluation of mir-612 (Rs12803915) Genetic Variant with Susceptibility to Pediatric Acute Lymphoblastic Leukemia. Reports of Biochemistry & Molecular Biology, 2021. 9(4): p. 385. [DOI:10.52547/rbmb.9.4.385]
7. Malard, F. and M. Mohty, Acute lymphoblastic leukaemia. The Lancet, 2020. 395(10230): p. 1146-1162. [DOI:10.1016/S0140-6736(19)33018-1]
8. Pui, C.-H., K.E. Nichols, and J.J. Yang, Somatic and germline genomics in paediatric acute lymphoblastic leukaemia. Nature reviews Clinical oncology, 2019. 16(4): p. 227-240. [DOI:10.1038/s41571-018-0136-6]
9. Cools, J., Improvements in the survival of children and adolescents with acute lymphoblastic leukemia. Haematologica, 2012. 97(5): p. 635-635. [DOI:10.3324/haematol.2012.068361]
10. Eche, I.J. and T. Aronowitz, A Literature Review of Racial Disparities in Overall Survival of Black Children With Acute Lymphoblastic Leukemia Compared With White Children With Acute Lymphoblastic Leukemia. Journal of Pediatric Oncology Nursing, 2020. 37(3): p. 180-194. [DOI:10.1177/1043454220907547]
11. Rudin, S., M. Marable, and R.S. Huang, The promise of pharmacogenomics in reducing toxicity during acute lymphoblastic leukemia maintenance treatment. Genomics, proteomics & bioinformatics, 2017. 15(2): p. 82-93. [DOI:10.1016/j.gpb.2016.11.003]
12. Ebbesen, M.S., et al., Hepatotoxicity during maintenance therapy and prognosis in children with acute lymphoblastic leukemia. Journal of pediatric hematology/oncology, 2017. 39(3): p. 161-166. [DOI:10.1097/MPH.0000000000000733]
13. Karppinen, S., O. Lohi, and M. Vihola, prediction of leukocyte counts during paediatric acute lymphoblastic leukaemia maintenance therapy. Scientific reports, 2019. 9(1): p. 1-11. [DOI:10.1038/s41598-019-54492-5]
14. Schmiegelow, K., et al., Mercaptopurine/methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. Journal of pediatric hematology/oncology, 2014. 36(7): p. 503. [DOI:10.1097/MPH.0000000000000206]
15. Conneely, S.E., S.L. Cooper, and R.E. Rau, Use of allopurinol to mitigate 6-mercaptopurine associated gastrointestinal toxicity in acute lymphoblastic leukemia. Frontiers in Oncology, 2020. 10. [DOI:10.3389/fonc.2020.01129]
16. Brandalise, S.R., et al., Shorter maintenance therapy in childhood acute lymphoblastic leukemia: the experience of the prospective, randomized brazilian GBTLI ALL-93 protocol. Frontiers in pediatrics, 2016. 4: p. 110. [DOI:10.3389/fped.2016.00110]
17. Kato, M., et al., Long-term outcome of six months maintenance chemotherapy for ALL in children: TCCSG L92-13E study. 2015, American Society of Clinical Oncology. [DOI:10.1200/jco.2015.33.15_suppl.10032]
18. Khaeso, K., et al., Genetic Polymorphisms of Drug-Metabolizing Enzymes Involved in 6-Mercaptopurine-Induced Myelosuppression in Thai Pediatric Acute Lymphoblastic Leukemia Patients. Journal of Pediatric Genetics, 2020. [DOI:10.1055/s-0040-1715818]
19. Nishii, R., et al., Preclinical evaluation of NUDT15-guided thiopurine therapy and its effects on toxicity and antileukemic efficacy. Blood, 2018. 131(22): p. 2466-2474. [DOI:10.1182/blood-2017-11-815506]
20. Lennard, L., et al., Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics. British journal of haematology, 2015. 169(2): p. 228-240. [DOI:10.1111/bjh.13240]
21. Chen, L., et al., Clinical efficacy and safety of 6-thioguanine in the treatment of childhood acute lymphoblastic leukemia: A protocol for systematic review and meta-analysis. Medicine (Baltimore), 2020. 99(18): p. e20082. [DOI:10.1097/MD.0000000000020082]
22. Jiang, C., et al., Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia. Clin Pharmacol Ther, 2020. [DOI:10.1101/2020.10.13.338384]
23. Evans, W.E., et al., Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. Journal of Clinical Oncology, 2001. 19(8): p. 2293-2301. [DOI:10.1200/JCO.2001.19.8.2293]
24. Farfan, M.J., et al., Prevalence of TPMT and ITPA gene polymorphisms and effect on mercaptopurine dosage in Chilean children with acute lymphoblastic leukemia. BMC cancer, 2014. 14(1): p. 299. [DOI:10.1186/1471-2407-14-299]
25. Azimi, F., et al., Frequency of ITPA gene polymorphisms in Iranian patients with acute lymphoblastic leukemia and prediction of its myelosuppressive effects. Leukemia research, 2015. 39(10): p. 1048-1054. [DOI:10.1016/j.leukres.2015.06.016]
26. Dorababu, P., et al., Epistatic interactions between thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) variations determine 6-mercaptopurine toxicity in Indian children with acute lymphoblastic leukemia. European journal of clinical pharmacology, 2012. 68(4): p. 379-387. [DOI:10.1007/s00228-011-1133-1]
27. Wang, D.-S., et al., Childhood acute lymphoblastic leukemia mercaptopurine intolerance is associated with NUDT15 variants. Pediatric Research, 2020: p. 1-6. [DOI:10.1038/s41390-020-0868-8]
28. Relling, M.V., et al., Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT 15 genotypes: 2018 update. Clinical Pharmacology & Therapeutics, 2019. 105(5): p. 1095-1105. [DOI:10.1002/cpt.1304]
29. Bahari, A., et al., Frequency of thiopurine S-methyltransferase (TPMT) alleles in southeast Iranian population. Nucleosides, Nucleotides and Nucleic Acids, 2010. 29(3): p. 237-244. [DOI:10.1080/15257771003720418]
30. Shriyan, B., et al., Novel NUDT15 germline variant in acute lymphoblastic leukaemia-Increase susceptibility to mercaptopurine toxicity responsible for relapse and severe life threatening sepsis: A case report. Pediatric Hematology Oncology Journal, 2017. 2(3): p. 65-67. [DOI:10.1016/j.phoj.2017.10.004]
31. Fei, X., et al., NUDT15 R139C variation increases the risk of azathioprine-induced toxicity in Chinese subjects: case report and literature review. Medicine, 2018. 97(17). [DOI:10.1097/MD.0000000000010301]
32. Gurwitz, D., et al., Improving pharmacovigilance in Europe: TPMT genotyping and phenotyping in the UK and Spain. Eur J Hum Genet, 2009. 17(8): p. 991-8. [DOI:10.1038/ejhg.2009.10]
33. Maamari, D., et al., Implementation of Pharmacogenetics to Individualize Treatment Regimens for Children with Acute Lymphoblastic Leukemia. Pharmacogenomics and Personalized Medicine, 2020. 13: p. 295. [DOI:10.2147/PGPM.S239602]
34. Cao, M., et al., Screening of Novel Pharmacogenetic Candidates for Mercaptopurine-Induced Toxicity in Patients With Acute Lymphoblastic Leukemia. Frontiers in Pharmacology, 2020. 11: p. 267. [DOI:10.3389/fphar.2020.00267]
35. Zhou, H., et al., Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants? BMC cancer, 2018. 18(1): p. 1-9. [DOI:10.1186/s12885-018-4398-2]
36. Yang, S.-K., et al., A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nature genetics, 2014. 46(9): p. 1017. [DOI:10.1038/ng.3060]
37. Yang, J.J., et al., Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. Journal of clinical oncology, 2015. 33(11): p. 1235. [DOI:10.1200/JCO.2014.59.4671]
38. Koutsilieri, S., et al., Optimizing thiopurine dosing based on TPMT and NUDT15 genotypes: it takes two to tango. Am. J. Hematol, 2019. 94(7): p. 737-740. [DOI:10.1002/ajh.25485]
39. Rehling, D., et al., Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity. Journal of Biological Chemistry, 2021. 296. [DOI:10.1016/j.jbc.2021.100568]
40. Carter, M., et al., Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2. Nature communications, 2015. 6(1): p. 1-10. [DOI:10.1038/ncomms8871]
41. Valerie, N.C., et al., NUDT15 hydrolyzes 6-thio-deoxyGTP to mediate the anticancer efficacy of 6-thioguanine. Cancer research, 2016. 76(18): p. 5501-5511. [DOI:10.1158/0008-5472.CAN-16-0584]
42. Moriyama, T., et al., NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet, 2016. 48(4): p. 367-73. [DOI:10.1038/ng.3508]
43. Moriyama, T., et al., Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry. Blood, 2017. 130(10): p. 1209-1212. [DOI:10.1182/blood-2017-05-782383]
44. Tsujimoto, S., et al., Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity in pediatric lymphoid neoplasms. Leukemia, 2018. 32(12): p. 2710-2714. [DOI:10.1038/s41375-018-0190-1]
45. Yi, E.S., et al., NUDT15 Variants Cause Hematopoietic Toxicity with Low 6-TGN Levels in Children with Acute Lymphoblastic Leukemia. Cancer Res Treat, 2018. 50(3): p. 872-882. [DOI:10.4143/crt.2017.283]
46. Kakuta, Y., et al., High-resolution melt analysis enables simple genotyping of complicated polymorphisms of codon 18 rendering the NUDT15 diplotype. J Gastroenterol, 2020. 55(1): p. 67-77. https://doi.org/10.1007/s00535-019-01638-x [DOI:10.1007/s00535-019-01646-x]
47. Kakuta, Y., et al., NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study. J Gastroenterol, 2018. 53(9): p. 1065-1078. [DOI:10.1007/s00535-018-1486-7]
48. Kakuta, Y., et al., NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD. Pharmacogenomics J, 2016. 16(3): p. 280-5. [DOI:10.1038/tpj.2015.43]
49. Khera, S., et al., Prevalence of TPMT, ITPA and NUDT 15 genetic polymorphisms and their relation to 6MP toxicity in north Indian children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol, 2019. 83(2): p. 341-348. [DOI:10.1007/s00280-018-3732-3]
50. Buaboonnam, J., et al., Effect of NUDT15 on incidence of neutropenia in children with acute lymphoblastic leukemia. Pediatr Int, 2019. 61(8): p. 754-758. [DOI:10.1111/ped.13905]
51. Zgheib, N.K., 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. Pediatric blood & cancer, 2017. 64(1): p. 146-150. [DOI:10.1002/pbc.26189]
52. Yang, X., et al., Rare gene variants in a patient with azathioprine-induced lethal myelosuppression. Annals of hematology, 2017. 96(12): p. 2131-2133. [DOI:10.1007/s00277-017-3112-9]
53. Tanaka, Y., 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): p. 109-15. [DOI:10.1111/bjh.13518]
54. Coenen, M.J., NUDT15 genotyping in Caucasian patients can help to optimise thiopurine treatment in patients with inflammatory bowel disease. Translational Gastroenterology and Hepatology, 2019. 4. [DOI:10.21037/tgh.2019.11.09]
55. Kim, H.T., et al., NUDT15 genotype distributions in the Korean population. Pharmacogenet Genomics, 2017. 27(5): p. 197-200. [DOI:10.1097/FPC.0000000000000274]
56. Soler, A.M., 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): p. 252-255. [DOI:10.1111/bjh.14532]
57. Kishibe, M., et al., Severe thiopurine-induced leukocytopenia and hair loss in Japanese patients with defective NUDT15 variant: Retrospective case-control study. J Dermatol, 2018. 45(10): p. 1160-1165. [DOI:10.1111/1346-8138.14588]
58. Suzuki, H., 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(9): p. 797-801. [DOI:10.1038/jhg.2016.55]
59. Kim, H., et al., Association of APEX1 and NUDT15 Polymorphisms with Mercaptopurine-Related Neutropenia in Pediatric Acute Lymphoblastic Leukemia. Blood, 2017. 130(Supplement 1): p. 1320-1320.
60. Choi, R., et al., Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia. British journal of clinical pharmacology, 2019. 85(7): p. 1585-1597. [DOI:10.1111/bcp.13943]
61. Chiengthong, K., 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): p. e24-6. [DOI:10.3324/haematol.2015.134775]
62. Zhou, Y., et al., Precision therapy of 6-mercaptopurine in Chinese children with acute lymphoblastic leukaemia. Br J Clin Pharmacol, 2020. 86(8): p. 1519-1527. [DOI:10.1111/bcp.14258]
63. Shah, S.A., et al., Preemptive NUDT15 genotyping: redefining the management of patients with thiopurine-induced toxicity. Drug metabolism and personalized therapy, 2018. 33(1): p. 57-60. [DOI:10.1515/dmpt-2017-0038]
64. Suiter, C.C., et al., Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity. Proc Natl Acad Sci U S A, 2020. 117(10): p. 5394-5401. [DOI:10.1073/pnas.1915680117]
65. Liang, D.C., et al., NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia. Pharmacogenomics J, 2016. 16(6): p. 536-539. [DOI:10.1038/tpj.2015.75]
66. Zhu, Y., et al., Combination of common and novel rare NUDT15 variants improves predictive sensitivity of thiopurine-induced leukopenia in children with acute lymphoblastic leukemia. Haematologica, 2018. 103(7): p. e293-e295. [DOI:10.3324/haematol.2018.187658]
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