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This cytidine analog depletes intracellular DNMT1, and it has been hypothesized that DNMT1 depletion leads to hypomethylation and de-repression of methylated tumor suppressor genes. We used a pre-clinical model of MDS to investigate the efficacy of 5-azacytidine. Unexpectedly, we found an increased frequency of acute lymphoid leukemia (ALL) in 5AZA treated mice. Whole exome sequencing (WES) revealed a large number of C\u2009&gt;\u2009G transversions in 5AZA treated mice, including genes known to be important for ALL such as\n                    <jats:italic>Chd4, Ikzf1<\/jats:italic>\n                    , and\n                    <jats:italic>Trp53<\/jats:italic>\n                    . Single base substitution (SBS) profiling revealed increased C\u2009&gt;\u2009G mutations in the ALL cells, with a mutation signature similar to the previously described SBS39 signature. An in vitro GEMINI (Genotoxic Mutational Signature Identified After Clonal Expansion In vitro) assay recapitulated the finding of increased C\u2009&gt;\u2009G mutations in both murine and human cell lines. Furthermore, similar GEMINI assays revealed induction of C\u2009&gt;\u2009G mutations in cells treated with decitabine. Taken together, these findings demonstrate that azanucleosides induce C\u2009&gt;\u2009G mutations both in vitro and in vivo, and are linked to leukemic transformation in murine cells.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02670-y","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T07:22:06Z","timestamp":1752823326000},"page":"2112-2124","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["5-Azacytidine and decitabine induce C\u2009&gt;\u2009G transversions in both murine and human cells"],"prefix":"10.1038","volume":"39","author":[{"given":"Ryan","family":"Bertoli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dengchao","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5455-7418","authenticated-orcid":false,"given":"Olivia","family":"Tuckey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0429-2189","authenticated-orcid":false,"given":"Susannah","family":"Gammell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Wokasch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang Jo","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason M.","family":"Foulks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5686-9969","authenticated-orcid":false,"given":"Peter D.","family":"Aplan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"2670_CR1","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1056\/NEJMra1904794","volume":"383","author":"M Cazzola","year":"2020","unstructured":"Cazzola M. 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