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

Autores: Ainciburu Fernandez, Marina; Berastegui Zufiaurre, Nerea; Romero Riojas, Juan Pablo; García Olloqui, Paula; Alfonso Piérola, Ana; Philippe, C.; Vilas Zornoza, Amaia; San Martín Úriz, Patxi; Ruiz Hernández, R.; Abarrategi, A.; Ordoñez, R.; Alignani, Diego Oscar; Sarvide Plano, Sarai; Castro Labrador, L.; Lamo de Espinosa Vázquez de Sola, José María; San Julián Aranguren, Miguel; Jimenez, T.; López Cadenas, F.; Muntion, S.; Sanchez Guijo, F.; Molero, A.; Montoro, M. J.; Tazón, B.; SERRANO SANZ, Guillermo; Díaz Mazquiaran, Aintzane; Hernaez Arrazola, Mikel; Huerga Domínguez, Sofia; Bewicke Copley, F.; Rio Machin, A.; Maurano, M.; Díez Campelo, M.; Valcarcel, D.; Rouault Pierre, K.; LARA ASTIASO, David; Ezponda Itoiz, Teresa; Prosper Cardoso, Felipe
Título de la revista: NATURE COMMUNICATIONS
ISSN: 2041-1723
Volumen: 13
Número: 1
Páginas: 7619
Fecha de publicación: 2022
Resumen:
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+ cells from MDS patients with anemia is able to restore erythropoiesis. These results identify DDIT3 as a driver of dyserythropoiesis, and a potential therapeutic target to restore the inefficient erythroid differentiation characterizing MDS patients. © 2022, The Author(s).