Targeted Inhibition of CREB for the Treatment of Pediatric Acute Myeloid Leukemia
The student will work on a project that involves the targeted inhibition of a transcription factor for the treatment of pediatric acute myeloid leukemia (AML). Pediatric patients with AML have low survival rates, although treatment has been improved with advancements in chemotherapy and stem cell transplantation. The transcription factor cAMP Response-Element Binding Protein (CREB) is overexpressed in the majority of patients with AML and is associated with a worse prognosis with increased risk or relapse and decreased event-free survival. Prior work showed that overexpression of CREB increases growth of AML cells, whereas the knockdown of CREB disrupts function of AML cells in vitro. Conversely, the knockdown of CREB does not affect long-term hematopoietic stem cell activity in murine model transduction/transplantation assays. These studies suggest that CREB could be a potential drug target for AML therapy.
To test this hypothesis, a small molecule inhibitor of CREB, XX-650-23, was developed. The molecule disrupts CREB-driven gene expression by blocking the interaction between CREB and its required co-activator, CREB Binding Protein (CBP). Prevention of this CREB-CBP interaction leads to apoptosis and cell-cycle arrest in AML cells, which increases the survival of murine models that have been injected with human AML cells. XX-650-23 demonstrates little toxicity on normal human hematopoietic cells and tissues in murine models. The Sakamoto lab performed RNA-seq, ChIP-seq and Cytometry Time of Flight with human AML cells to better understand the mechanism of XX-650-23. The results showed that the inhibition of CREB-CBP interactions mainly affected apoptotic, cell-cycle and survival pathways. Further research may lead to a better understanding of the pathogenesis of AML and novel therapies for AML.
Mentored by Dr. Kathleen Sakamoto
Stanford University, Stanford, CA