Modeling and Characterizing the Genomic Consequences of MED12 Mutations in Uterine Fibroids - ABSTRACT Uterine fibroids (leiomyomas) are the most widely observed tumors in women. By age 50, more than ~70% of white and more than 80% of black women develop at least one UF tumor. Although non-malignant, they disrupt normal uterine function and cause severe health problems ~25% of reproductive-age women. The most common subtype, representing ~70% of all fibroids, is caused by recurrent somatic mutations in the MED12 gene that encodes the mediator of transcription subunit 12 (MED12) protein. The lack of proper model systems hampered our mechanistic understanding of UF development and identifying effective treatment strategies. Our long-term goal is to interrogate the functional role of driver genetic mutations in fibroid tumors and identify potential targetable mechanisms downstream of these mutations. Our objective in this proposal, a critical step toward our long-term goal, is to create and exploit disease-relevant human cellular models of UF by CRISPR engineering specific MED12 mutations, decipher their functional role in driving UF tumorigenesis and identify druggable mechanisms to target mutant cells selectively.
