Children's Hospital of Wisconsin Archives

2014

Scholar Grant

Dr. Sridhar Rao

Milwaukee, WI

Acute myelogenous leukemia (AML) remains a significant clinical problem in pediatric oncology, with an overall survival of approximately 50%, even in the face of highly toxic therapies. This emphasizes the need for more targeted, less-harmful therapies. Recent genome-wide approaches have illustrated that AML is a genetically heterogeneous disease, with a wide range of mutations in different patients. This illustrates that “driver” mutations likely create a “context”, or genetic milieu that then requires additional secondary hits to cause leukemia development and/or progression. The cohesin complex is a multiple-protein complex with multiple functions, including cell-division and the regulation of gene expression. Cohesin mutations are present in a minority of AML patients (5-20%) with no clear evidence for how they may function in leukemogenesis. Our own lab focuses on the cohesin complex in a variety of model systems, and recently has uncovered that the cohesin complex has a critical role in Polycomb Repressive Complex 2 (PRC2) function, a critical epigenetic regulatory. Our preliminary data indicates that the cohesin complex causes genes normally silenced by the PRC2 complex to become expressed. In addition, depleting the cohesin complex in an in vitro model of AML known to require the PRC2 complex shows decreased leukemia formation. Collectively, our preliminary data indicates that mutations in the cohesin complex may play a role in AML by altering PRC2 function. We propose to study this further in vivo to assess the role of the cohesin complex on AML generated by two different driver mutations to understand how the cohesin complex plays a role in leukemogenesis in a context-specific fashion.