PLK1 inhibition induces synthetic lethality in Fanconi anemia pathway-deficient acute myeloid leukemia
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Fusion Lumos
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Amber Mosley
PROVIDER: MSV000096625 | MassIVE | Mon Dec 09 12:43:00 GMT 2024
SECONDARY ACCESSION(S): PXD058705
REPOSITORIES: MassIVE
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Project description:The Fanconi anemia (FA) pathway is a network of proteins critical to the preservation of genomic integrity and the prevention of cancer. FA proteins safeguard the genome by regulating the cell cycle and facilitating error-free repair of DNA damage. Bi-allelic mutation of genes encoding FA pathway proteins causes the cancer predisposition syndrome Fanconi anemia (FA), which is associated with a high incidence of acute myeloid leukemia (AML). Individuals with mono-allelic mutation of a subset FA genes do not develop FA but suffer increased lifetime risk of solid and hematological malignancies. Within the general population, approximately 14% of sporadic AMLs harbor damaging mutations within the FA pathway. Our previous work demonstrated that inhibition of the mitotic kinase PLK1 induced synthetic lethality in cells deficient for FANCA, the gene most frequently lost in FA. This finding corroborates work from others that have identified synthetic lethal interactions between PLK1 and additional FA genes (FANCG, BRCA1, and BRCA2). Together, these findings suggest that FA pathway mutations may serve as biomarkers for sensitivity to PLK1 inhibitors, which have demonstrated therapeutic efficacy in an undefined subset of AML patients. Here, HL60 AML cells were generated with shControl or shFANCA and treated with 10nM volasertib for 24 h prior to kinome profiling.
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