Clapp, D. WadeSheth, Aditya SukumarVance, GailAngus, SteveHerbert, Brittney-Shea2023-08-162023-08-162023-07https://hdl.handle.net/1805/34938Indiana University-Purdue University Indianapolis (IUPUI)The Fanconi anemia (FA) signaling network plays a critical role in maintaining genomic integrity during interphase and mitosis. Biallelic germline mutation of any of the 22 genes that constitute this pathway (FANCA-FANCW) results in Fanconi Anemia, a cancer predisposition syndrome characterized by congenital malformations, bone marrow failure, and pediatric acute myeloid leukemias (AMLs). Among the general population, acquired genetic disruptions of the FA pathway are found in 30% of all sporadic cancers and over 15% of sporadic pediatric AMLs underscoring the importance of this pathway in the prevention of malignant transformation. Therefore, the identification of precision therapies for FA-deficient AML is a critical need. The canonical tumor suppressive role of FA proteins in the repair of DNA damage during interphase is well established. We and others have uncovered the roles of FA proteins in mitotic regulation, suggesting additional mechanisms by which the FA pathway prevents genomic instability. Mutation of FANCA is the most common cause of FA and is one of the most frequently disrupted FA pathway genes in sporadic AML. To identify synthetic lethal targets of FANCA, we previously identified mitotic phospho-signaling pathways required for the survival of FANCA-/- patient-derived fibroblasts through a kinome-wide shRNA screen. We identified mitotic kinases CHEK1, PLK1, SLK, and TTK as potential targets, which suggests a mitosis-specific vulnerability of FA-deficient cells. These findings corroborate work by others who have identified synthetic lethal interactions between PLK1 and the FA pathway members, FANCG and BRCA1, suggesting that inactivation of the FA pathway may sensitize cancers to PLK1 inhibition. A more thorough understanding of FA pathway function in mitosis provides new insight into AML pathogenesis and suggests that genetic disruptions of the FA pathway may be predictive of sensitivity to PLK1 inhibition, providing a preclinical rationale for the development of precision therapies.en-USAMLCancerDNA damageFanconi AnemiaMitosisPrecision therapyDissertation