MassIVE MSV000096625

Partial Public PXD058705

PLK1 inhibition induces synthetic lethality in Fanconi anemia pathway-deficient acute myeloid leukemia

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Description

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 AML patients. 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. Here, 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 chromosomes, and triggers mitotic collapse in FANCA-deficient cells. Our findings indicate that PLK1 inhibition targets mitotic vulnerabilities specific to FA pathway-deficient cells and implicate FA pathway mutations as potential biomarkers for the identification of patients likely to benefit from PLK1 inhibitors. [doi:10.25345/C5V11VZ0W] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: acute myeloid leukemia ; PLK1 ; Fanconi anemia (FA) pathway ; mitotic collapse ; DatasetType:Proteomics

Contact

Principal Investigators:
(in alphabetical order) 		Amber Mosley, Indiana University School of Medicine, United States
Submitting User: edoud

Publications

Sheth AS, Chan KK, Liu S, Wan J, Angus SP, Rhodes SD, Mitchell DK, Davis C, Ridinger M, Croucher PJ, Zeidan AM, Wijeratne A, Qian S, Tran NT, Sierra Potchanant EA.
PLK1 Inhibition Induces Synthetic Lethality in Fanconi Anemia Pathway-Deficient Acute Myeloid Leukemia.
Cancer Res Commun. 2025 Apr 1;5(4):648-667.

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