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Recently, we reported that regional DNA hypermethylation in HTLV\u20101\u2010infected T\u2010cells reflects the disease status of ATL and the anti\u2010ATL effects of DNA demethylating agents, including azacitidine (AZA), decitabine (DAC) and a new DAC prodrug, OR\u20102100 (OR21), which we developed. Here, to better understand the mechanisms underlying drug resistance, we generated AZA\u2010, DAC\u2010 and OR21\u2010resistant (AZA\u2010R, DAC\u2010R and OR21\u2010R, respectively) cells from the ATL cell line TL\u2010Om1 and the HTLV\u20101\u2010infected cell line MT\u20102 via long\u2010term drug exposure. The efficacy of OR21 was almost the same as that of DAC, indicating that the pharmacodynamics of OR21 were due to release of DAC from OR21. Resistant cells did not show cellular responses observed in parental cells induced by treatment with drugs, including growth suppression, depletion of DNA methyltransferase DNMT1 and DNA hypomethylation. We also found that reduced expression of deoxycytidine kinase (DCK) correlated with lower susceptibility to DAC\/OR21 and that reduced expression of uridine cytidine kinase2 (UCK2) correlated with reduced susceptibility to AZA. DCK and UCK2 catalyze phosphorylation of DAC and AZA, respectively; reconstitution of expression reversed the resistant phenotypes. A large homozygous deletion in <jats:italic>DCK<\/jats:italic> and a homozygous splice donor site mutation in <jats:italic>UCK2<\/jats:italic> were identified in DAC\u2010R TL\u2010Om1 and AZA\u2010R TL\u2010Om1, respectively. Both genomic mutations might lead to loss of protein expression. Thus, inactivation of UCK2 and DCK might be a putative cause of phenotypes that are resistant to AZA and DAC\/OR21, respectively.<\/jats:p>","DOI":"10.1002\/ijc.33901","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T12:37:50Z","timestamp":1639658270000},"page":"1184-1197","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Adult T\u2010cell leukemia\u2010lymphoma acquires resistance to <scp>DNA<\/scp> demethylating agents through dysregulation of enzymes involved in pyrimidine metabolism"],"prefix":"10.1002","volume":"150","author":[{"given":"Nao","family":"Yoshida\u2010Sakai","sequence":"first","affiliation":[{"name":"Department of Drug Discovery and Biomedical Sciences, Faculty of Medicine Saga University  Saga Japan"},{"name":"Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine Saga University  Saga 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