Biallelic CEBPA mutations alter chromatin accessibility and STAT activation

The overall aim of this work is to understand how biallelic CEBPA mutations block differentiation and contributed to the development of acute myeloid leukemia (AML). This work shows that biallelic mutant Cebpa cells exhibit downregulation of gene expression programs involved in myeloid differentiation as well as altered chromatin accessibility and subsequent loss of CEBPA binding to its canonical regulatory gene elements. Additionally, it shows that CEBPA cooperates with STAT3 to regulate expression of differentiation associated genes, and that genes with overlapping CEBPA and STAT3 peaks are protected in biallelic mutant Cebpa cells with a cooperating CSF3R mutation Together, these data implicate a dependence on activated STAT signaling for oncogenesis in biallelic Cepba mutant AML.