Targeting a CDH1–TK1–dependent DNA Synthesis Pathway Overcomes Chemoresistance in Acute Myeloid Leukemia
TL;DR
Findings define a CDH1‐TK1‐associated program that promotes salvage‐dependent replication stress tolerance and nominate TK1 as a candidate biomarker for replication stress‐targeted therapy.
Abstract
Relapsed and refractory acute myeloid leukemia (AML) remains difficult to treat, in part because leukemic cells adapt to nucleoside analogue‐induced replication stress. 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 Mll‐Af9/Setd2‐mutant 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 Tk1 impaired DNA synthesis, increased replication‐associated DNA damage, and restored chemosensitivity. Mechanistically, TK1 accumulation was linked to impaired APC/C‐CDH1 activity, and manipulation of Cdh1 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‐derived xenograft models, this combination reduced leukemic burden and prolonged survival, particularly in TK1‐high AML. These findings define a CDH1‐TK1‐associated program that promotes salvage‐dependent replication stress tolerance and nominate TK1 as a candidate biomarker for replication stress‐targeted therapy.