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Here, we identify thymidine kinase 1 (TK1) as a functional contributor to chemotherapy resistance in AML. Integrated analyses of TCGA, Beat AML, and murine chemoresistant AML transcriptomes revealed that high TK1 expression was associated with adverse outcome, cytarabine resistance, and enrichment of nucleotide salvage programs. In\n                    <jats:italic>Mll\u2010Af9\/Setd2<\/jats:italic>\n                    \u2010mutant AML cells, TK1 upregulation coincided with reduced de novo nucleotide synthesis, sustained BrdU incorporation, attenuated replication stress signaling, and resistance to daunorubicin plus cytarabine. Genetic suppression of\n                    <jats:italic>Tk1<\/jats:italic>\n                    impaired DNA synthesis, increased replication\u2010associated DNA damage, and restored chemosensitivity. Mechanistically, TK1 accumulation was linked to impaired APC\/C\u2010CDH1 activity, and manipulation of\n                    <jats:italic>Cdh1<\/jats:italic>\n                    altered TK1 abundance, replication stress tolerance, and drug response. Combined topoisomerase I and WEE1 inhibition increased CDH1 expression, reduced TK1 abundance, enforced replication stress, and induced leukemic cell death. In relapsed\/refractory AML patient\u2010derived xenograft models, this combination reduced leukemic burden and prolonged survival, particularly in TK1\u2010high AML. These findings define a CDH1\u2010TK1\u2010associated program that promotes salvage\u2010dependent replication stress tolerance and nominate TK1 as a candidate biomarker for replication stress\u2010targeted therapy.\n                  <\/jats:p>","DOI":"10.1002\/hon.70238","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T17:50:50Z","timestamp":1786211450000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting a CDH1\u2013TK1\u2013dependent DNA Synthesis Pathway Overcomes Chemoresistance in Acute Myeloid Leukemia"],"prefix":"10.1002","volume":"44","author":[{"given":"Xiaomin","family":"Feng","sequence":"first","affiliation":[{"name":"Clinical Research Centre Guangdong Clifford Hospital  Guangzhou China"},{"name":"Joe R. and Teresa Lozano Long School of Medicine UT Health San Antonio Mays Cancer Center  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Huo","sequence":"additional","affiliation":[{"name":"Department of Hematology The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clifford","family":"Pang","sequence":"additional","affiliation":[{"name":"Clinical Research Centre Guangdong Clifford Hospital  Guangzhou China"},{"name":"Guangzhou Wellness Stem Cell Research Co. 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Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology The First Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8928-8367","authenticated-orcid":false,"given":"Yujuan","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Peking University People's Hospital Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7381-6236","authenticated-orcid":false,"given":"Huimin","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Peking University People's Hospital Peking University  Beijing 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