Mutant CEBPA promotes tolerance to inflammatory stress through deficient AP-1 activation

• DOI: 10.1038/s41467-025-58712-7
• Publication Date: 2025-04-12T20:42:45Z
• Authors: Maria Cadefau-Fab...; Gerard Martínez-C...; Lucía Lorenzi; Felix D. Weiss; Anne-Katrine Frank; José Manuel Caste...; Eric Julià-Vilella; Andrés Gámez-García; Laura Yera; Carini Picardi Mo...; Yi-Fang Wang; Felix Meissner; Alejandro Vaquero; Matthias Merkensc...; Bo T. Porse; Sergi Cuartero

Abstract 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 arise from the differential regulation of AP-1 family proteins. In addition, we find that the impaired function of the AP-1 member ATF4 in p30-expressing cells alters their response to ER stress. Collectively, these findings uncover a link between mutant CEBPA, inflammation and the stress response, potentially revealing a vulnerability in AML.