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The transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes

2022; Nature Portfolio; Volume: 13; Issue: 1 Linguagem: Inglês

10.1038/s41467-022-35192-7

2041-1723

Nerea Berastegui, Marina Ainciburu, Juan P. Romero, Paula García‐Olloqui, Ana Alfonso Piérola, Céline Philippe, Amaia Vilas‐Zornoza, Patxi San Martín‐Uriz, Raquel Ruiz-Hernández, Ander Abarrategi, Raquel Ordóñez, Diego Alignani, Sarai Sarvide, Laura Castro‐Labrador, José María Lamo-Espinosa, Mikel San-Julián, Tamara Jiménez, Félix López Cadenas, Sandra Muntión, Fermín Sánchez‐Guijo, Antonieta Molero, María Julia Montoro, Bárbara Tazón‐Vega, Guillermo Serrano, Aintzane Díaz-Mazkiaran, Mikel Hernáez, Sofía Huerga, Findlay Bewicke‐Copley, Ana Rio‐Machín, Matthew T. Maurano, María Díez‐Campelo, David Valcárcel, Kevin Rouault‐Pierre, David Lara‐Astiaso, Teresa Ezponda, Felipe Prósper,

Immune Cell Function and Interaction

Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis, with increased incidence in older individuals. Here we analyze the transcriptome of human HSCs purified from young and older healthy adults, as well as MDS patients, identifying transcriptional alterations following different patterns of expression. While aging-associated lesions seem to predispose HSCs to myeloid transformation, disease-specific alterations may trigger MDS development. Among MDS-specific lesions, we detect the upregulation of the transcription factor DNA Damage Inducible Transcript 3 (DDIT3). Overexpression of DDIT3 in human healthy HSCs induces an MDS-like transcriptional state, and dyserythropoiesis, an effect associated with a failure in the activation of transcriptional programs required for normal erythroid differentiation. Moreover, DDIT3 knockdown in CD34