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

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.

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Publication Details

Journal
Nature Communications
Published
2025-04-12
DOI
https://doi.org/10.1038/s41467-025-58712-7
Citations
7
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
12.39

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article

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

Maria Cadefau, Carini Picardi Morais de Castro, Bo Porse, Andrés Gámez-García et al.
7 citations
Nature Communications
Acute Myeloid Leukemia Research
12.39
article

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

Maria Cadefau, Carini Picardi Morais de Castro, Bo Porse, Andrés Gámez-García, Gerard Martínez-Cebrián, Sergi Cuartero, Lucía Lorenzi, Felix D. Weiss, Matthias Merkenschlager, Felix Meissner, Anne-Katrine Frank, Eric Julià-Vilella, José Manuel Castelló-García, Yi-Fang Wang, Alejandro Vaquero, Laura Yera
article en
7 citations

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.

Nature CommunicationsVol. 16(1)
University of Copenhagen (DK), University Hospital Bonn (DE), Copenhagen University Hospital (DK), Josep Carreras Leukaemia Research Institute (ES), Institute for Research in Biomedicine (ES), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), MRC London Institute of Medical Sciences (GB), Imperial College London (GB), Universitat de Barcelona (ES)
Washington University in St. Louis, European Commission, Novo Nordisk, Ministerio de Ciencia e Innovación, Fundación Josep Carreras Contra la Leucemia, Novo Nordisk Fonden, HORIZON EUROPE Framework Programme, Medical Research Council, Agència de Gestió d'Ajuts Universitaris i de Recerca, H2020 Marie Skłodowska-Curie Actions
Good health and well-being
Openalex Percentile: Top 1%
Acute Myeloid Leukemia Research
12.39
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