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It has also been demonstrated that acquired somatic mutations of the <jats:italic>NT5C2<\/jats:italic> and <jats:italic>PRPS1<\/jats:italic> genes, which are involved in thiopurine metabolism, are detectable in a portion of relapsed childhood ALL. To directly confirm the significance of the <jats:italic>NUDT15<\/jats:italic> variant genotype and <jats:italic>NT5C2<\/jats:italic> and <jats:italic>PRPS1<\/jats:italic>\u00a0mutations in thiopurine sensitivity of leukaemia cells in the intrinsic genes, we investigated 84 B\u2010cell precursor\u2010ALL (BCP\u2010ALL) cell lines. Three and 14 cell lines had homozygous and heterozygous variant diplotypes of the <jats:italic>NUDT15<\/jats:italic>\u00a0gene, respectively, while 4 and 2 cell lines that were exclusively established from the samples at relapse had the <jats:italic>NT5C2<\/jats:italic> and <jats:italic>PRPS1<\/jats:italic> mutations, respectively. Both <jats:italic>NUDT15<\/jats:italic> variant genotype and <jats:italic>NT5C2<\/jats:italic> and <jats:italic>PRPS1<\/jats:italic>\u00a0mutations were significantly associated with DNA\u2010incorporated thioguanine levels after exposure to thioguanine at therapeutic concentration. Considering the continuous exposure during the maintenance therapy, we evaluated in vitro mercaptopurine sensitivity after 7\u2010day exposure. Mercaptopurine concentrations lethal to 50% of the leukaemia cells were comparable to therapeutic serum concentration of mercaptopurine. Both <jats:italic>NUDT15<\/jats:italic> variant genotype and <jats:italic>NT5C2<\/jats:italic> and <jats:italic>PRPS1<\/jats:italic>\u00a0mutations were significantly associated with mercaptopurine sensitivity in 83 BCP\u2010ALL and 23\u00a0T\u2010ALL cell lines. The present study provides direct evidence to support the general principle showing that both inherited genotype and somatically acquired mutation are crucially implicated in the drug sensitivity of leukaemia cells.<\/jats:p>","DOI":"10.1111\/jcmm.16981","type":"journal-article","created":{"date-parts":[[2021,10,15]],"date-time":"2021-10-15T17:17:44Z","timestamp":1634318264000},"page":"10521-10533","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["<i>NUDT15<\/i> polymorphism and <i>NT5C2<\/i> and <i>PRPS1<\/i> mutations influence thiopurine sensitivity in acute lymphoblastic leukaemia cells"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5153-4545","authenticated-orcid":false,"given":"Shinpei","family":"Somazu","sequence":"first","affiliation":[{"name":"Department of Pediatrics University of Yamanashi Yamanashi 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