Mutant CEBPA promotes tolerance to inflammatory stress through deficient AP-1 activation [ChIP-seq]

The CEBPA transcription factor is frequently mutated in acute myeloid leukemia (AML). Mutations in the CEBPA gene, which are typically biallelic, result in the production of a shorter isoform known as p30. Both the canonical 42-kDa isoform (p42) and the AML-associated p30 isoform bind chromatin and activate transcription, but the specific transcriptional programs controlled by each protein and how they are linked to a selective advantage in AML is not well understood. Here, we show that cells expressing the AML-associated p30 have reduced baseline inflammatory gene expression and display altered dynamics of transcriptional induction in response to LPS, consequently impacting cytokine secretion. This confers p30-expressing cells an increased resistance to the adverse effects of prolonged exposure to inflammatory signals. Mechanistically, we show that these differences primarily result from the differential regulation of AP-1 family proteins. In addition, we find that the altered function of the AP-1 member ATF4 in p30-expressing cells alters their response to ER stress. Collectively, these findings uncover a novel link between mutant CEBPA, inflammation and the stress response, potentially revealing a new vulnerability in AML. Overall design: Chromatin immunoprecipitation (ChIP) was performed for histone marks (H3K27ac and H3K4me1), ATF4 and CEBPA transgenes by using an antibody targeting the ERT2 fusion fragment and using an antibody against CEBPA. LPS was added for 2 hours to induce an inflammatory response. Tunicamycin (Tm) was added at 2ug/mL to induce endogenous ATF4 translation