biostudies-literatureSheth ASNHLBI NIH HHSNCI NIH HHS648-667https://www.ebi.ac.uk/biostudies/studies/S-EPMC12011380biostudies-literatureUnknown5(4)<h4>Abstract</h4>Overall survival of acute myeloid leukemia (AML) remains limited. Inhibitors of the master mitotic kinase PLK1 have emerged as promising therapeutics, demonstrating efficacy in an undefined subset of patients with AML. However, the clinical success of PLK1 inhibitors remains hindered by a lack of predictive biomarkers. The Fanconi anemia (FA) pathway, a tumor-suppressive network comprised of at least 22 genes, is frequently mutated in sporadic AML. In this study, we demonstrate that FA pathway disruption sensitizes AML cells to PLK1 inhibition. Mechanistically, we identify novel interactions between PLK1 and both FANCA and FANCD2 at mitotic centromeres. We demonstrate that PLK1 inhibition impairs recruitment of FANCD2 to mitotic centromeres, induces damage to mitotic chromCancer research communicationsPLK1 Inhibition Induces Synthetic Lethality in Fanconi Anemia Pathway-Deficient Acute Myeloid Leukemia.PMC12011380P30 CA082709R01 HL132921Ridinger MTran NTAngus SPLiu SChan KKQian SWijeratne ADavis CWan JRhodes SDCroucher PJSheth ASMitchell DKZeidan AMSierra Potchanant EAfalsePLK1 Inhibition Induces Synthetic Lethality in Fanconi Anemia Pathway-Deficient Acute Myeloid Leukemia.<h4>Abstract</h4>Overall survival of acute myeloid leukemia (AML) remains limited. Inhibitors of the master mitotic kinase PLK1 have emerged as promising therapeutics, demonstrating efficacy in an undefined subset of patients with AML. However, the clinical success of PLK1 inhibitors remains hindered by a lack of predictive biomarkers. The Fanconi anemia (FA) pathway, a tumor-suppressive network comprised of at least 22 genes, is frequently mutated in sporadic AML. In this study, we demonstrate that FA pathway disruption sensitizes AML cells to PLK1 inhibition. Mechanistically, we identify novel interactions between PLK1 and both FANCA and FANCD2 at mitotic centromeres. We demonstrate that PLK1 inhibition impairs recruitment of FANCD2 to mitotic centromeres, induces damage to mitotic chrom2025-01-01T00:00:00Z2025 Apr2026-07-15T11:05:26.521Z2025-07-03T03:05:22.28ZS-EPMC120113804011112210.1158/2767-9764.CRC-24-0260