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

Maria Cadefau-Fabregat, Gerard Martínez-Cebrián, Lucía Lorenzi, Felix D. Weiss, Anne-Katrine Frank, José Manuel Castelló-García, Eric Julià-Vilella, Andrés Gámez-García, Laura Yera, Carini Picardi Morais de Castro, Yi-Fang Wang, Felix Meissner, Alejandro Vaquero, Matthias Merkenschlager, Bo T. Porse and Sergi Cuartero ()
Additional contact information
Maria Cadefau-Fabregat: Josep Carreras Leukaemia Research Institute (IJC)
Gerard Martínez-Cebrián: Josep Carreras Leukaemia Research Institute (IJC)
Lucía Lorenzi: Josep Carreras Leukaemia Research Institute (IJC)
Felix D. Weiss: University of Bonn
Anne-Katrine Frank: Copenhagen University Hospital—Rigshospitalet
José Manuel Castelló-García: Josep Carreras Leukaemia Research Institute (IJC)
Eric Julià-Vilella: Josep Carreras Leukaemia Research Institute (IJC)
Andrés Gámez-García: Josep Carreras Leukaemia Research Institute (IJC)
Laura Yera: Josep Carreras Leukaemia Research Institute (IJC)
Carini Picardi Morais de Castro: Josep Carreras Leukaemia Research Institute (IJC)
Yi-Fang Wang: Du Cane Road
Felix Meissner: University of Bonn
Alejandro Vaquero: Josep Carreras Leukaemia Research Institute (IJC)
Matthias Merkenschlager: Du Cane Road
Bo T. Porse: Copenhagen University Hospital—Rigshospitalet
Sergi Cuartero: Josep Carreras Leukaemia Research Institute (IJC)

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58712-7

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