Inhibition of CREB as a Target for Acute Myeloid Leukemia

Background:

Acute Myeloid Leukemia (AML) is one of the most challenging pediatric cancers to treat, with current therapies yielding a 50% 5-year overall survival. Previous studies have reported that CREB (cyclic AMP Response Element Binding protein), a transcription factor critical for AML cell survival and proliferation, is overexpressed in the majority of AML patients and is associated with a poor prognosis. Thus, our overall hypothesis is that CREB blockade represents a novel, effective approach to treat AML. We developed a small molecule inhibitor of CREB, XX-650-23, which blocks its interaction with its co-activator, the histone acetyltransferase CBP (CREB-Binding Protein).  CREB inhibition by XX-650-23 causes AML cell death and prolongs survival in mouse models of AML without toxicity. Whole transcriptome sequencing data suggests that CREB inhibition induces DNA damage and apoptosis in AML cells.

Project Goal:

The goal of this project is to characterize the mechanisms by which CREB blockade causes DNA damage and apoptosis through gene expression analysis and biochemical assays. These experiments will increase our understanding of the role of CREB in AML cell survival and potentially lay the groundwork for the development of a new family of targeted chemotherapy drugs.