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These AZA-resistant variants differ in their responses to other cytosine nucleoside analogs, including 5-aza-2\u2032-deoxycytidine (DAC), as well as in some molecular features. Differences in global DNA methylation, protein levels of DNA methyltransferases, and phosphorylation of histone H2AX were observed in response to AZA and DAC treatment in these cell variants. This could be due to changes in the expression of uridine-cytidine kinases 1 and 2 (UCK1 and UCK2) demonstrated in our cell variants. In the M\/A variant that retained sensitivity to DAC, we detected a homozygous point mutation in UCK2 resulting in an amino acid substitution (L220R) that is likely responsible for AZA resistance. Cells administered AZA treatment can switch to de novo synthesis of pyrimidine nucleotides, which could be blocked by inhibition of dihydroorotate dehydrogenase by teriflunomide (TFN). This is shown by the synergistic effect of AZA and TFN in those variants that were cross-resistant to DAC and did not have a mutation in UCK2.<\/jats:p>","DOI":"10.3390\/cancers15113063","type":"journal-article","created":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T02:08:15Z","timestamp":1686017295000},"page":"3063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Resistance of Leukemia Cells to 5-Azacytidine: Different Responses to the Same Induction Protocol"],"prefix":"10.3390","volume":"15","author":[{"given":"Krist\u00edna","family":"\u0160imoni\u010dov\u00e1","sequence":"first","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, D\u00fabravsk\u00e1 cesta 9, 84005 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubos","family":"Janotka","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, D\u00fabravsk\u00e1 cesta 9, 84005 Bratislava, Slovakia"},{"name":"Department of Biology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, 77515 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Kavcova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, D\u00fabravsk\u00e1 cesta 9, 84005 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7603-4491","authenticated-orcid":false,"given":"Zdena","family":"Sulova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, D\u00fabravsk\u00e1 cesta 9, 84005 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Messingerova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, D\u00fabravsk\u00e1 cesta 9, 84005 Bratislava, Slovakia"},{"name":"Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinsk\u00e9ho 9, 81237 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2174-786X","authenticated-orcid":false,"given":"Albert","family":"Breier","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, D\u00fabravsk\u00e1 cesta 9, 84005 Bratislava, Slovakia"},{"name":"Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinsk\u00e9ho 9, 81237 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"60","DOI":"10.6004\/jnccn.2017.0007","article-title":"Myelodysplastic Syndromes, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology","volume":"15","author":"Greenberg","year":"2017","journal-title":"J. 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