Presentation description

Acute myeloid leukemia (AML) is characterized by clonal proliferation of myeloid blasts. Prognosis is poor for patients diagnosed with the cancer, with a five year survival rate of just 30%. Advancing therapies have improved survival, though there remains the necessity for additional therapies targeting tumor survival and proliferation. Proteasomal degradation through post-translational ubiquitinylation by the ubiquitin proteasome system (UPS) is essential for normal cell signaling, differentiation, proliferation, and apoptosis pathways. A key player of the UPS is the SCF complex, which consists of its main scaffold proteins SKP and Cul1, with the FBOX domain being responsible for substrate recognition-making it a prime target for drug modulation. There are 72 known FBOX proteins with only 16 being well characterized in hematopoiesis. Fbxo3 substrates include HIPK2 & p300, Smurf-1, and fbxl2, which regulate cell differentiation/apoptosis, BMP signaling, and inflammation pathways respectively. Regulation of these signaling proteins indicates the potential of fbxo3 as a novel therapeutic target in AML. Patient data sets show that increased expression of fbxo3 leads to decreased survival, while fbxo3 expression is decreased in most AML cases. ShRNA knockdown of fbxo3 in MOLM-13 cells increased colony formation, as well as decreasing apoptosis as measured by flow cytometry. These results confirm that fbxo3 could indeed be a potential therapeutic target for drug modulation in AML. Future directions include immunoprecipitation and mass spectrometry to determine novel substrates unique to cancer types for more specific interaction inhibition, as well as KD and overexpression in primary patient AML samples.