3215 – TWO NOVEL ENHANCERS OF CDKN1A ARE EPIGENETICALLY REGULATED BY THE CHROMATIN ASSEMBLY FACTOR 1 AND CEBPA IN ACUTE MYELOID LEUKEMIA

Acute myeloid leukemia (AML) is a blood cancer frequently driven by epigenetic dysregulation that leads to myeloid differentiation blockage and unlimited expansion of myeloid blasts (AML cells). The cell cycle progression of AML cells is precisely under control of multiple regulators. Cyclin dependent kinase inhibitor 1A (CDKN1A) is such a regulatory factor and has multifaceted roles in determining AML cell fate. Our chromatin mapping analysis in AML cell lines identified two unreported enhancers near CDKN1A gene where the Chromatin Assembly Factor 1 (CAF1) complex, a master epigenetic regulator of leukemia cell fate, and the pro-myeloid transcription factor CEBPA exhibited antagonistic binding profile. The correlation analysis from DepMap portal database indicated that CAF1 expression is negatively correlated with CDKN1A expression in AML. By contrast, CEBPA and CDKN1A expression indicated a positive correlation. We further demonstrated that CDKN1A expression was regulated by the CAF1 and CEBPA antagonization. Specifically, CAF1 repressed while CEBPA activated the transcription of CDKN1A in AML cell lines. Further understanding of whether these two enhancers are critical for leukemogenesis will be achieved through deletion of the enhancer regions using CRISPR/Cas9 followed by in vitro functional assays and in vivo engraftment.