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

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 asMDS patients, identifying...

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Detalles Bibliográficos
Autores: Berastegui, Nerea, Ainciburu, Marina, Romero, Juan P., Garcia-Olloqui, Paula, Alfonso-Pierola, Ana, Philippe, Céline, Vilas-Zornoza, Amaia, San Martin-Uriz, Patxi, Ruiz-Hernández, Raquel, Abarrategi, Ander, Ordoñez, Raquel, Alignani, Diego, Sarvide, Sarai, Castro-Labrador, Laura, Lamo de Espinosa Vázquez de Sola, José María, San‑Julián, Mikel, Jimenez, Tamara, López Cadenas, Félix, Muntion, Sandra, Sanchez-Guijo, Fermín, Molero, Antonieta, Montoro, Julia
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universidad Católica de Valencia San Vicente Mártir
Repositorio:RIUCV. Repositorio de la Universidad Católica de Valencia San Vicente Mártir
Idioma:inglés
OAI Identifier:oai:riucv.ucv.es:20.500.12466/5216
Acceso en línea:http://hdl.handle.net/20.500.12466/5216
Access Level:acceso abierto
Palabra clave:Ageing
Haematopoietic stem cells
Myelodysplastic syndrome
Transcriptomics
3205.04 Hematología
Descripción
Sumario: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 asMDS 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 MDSspecific lesions, we detect the upregulation of the transcription factor DNA Damage Inducible Transcript 3 (DDIT3). Overexpression of DDIT3 in human healthyHSCs induces anMDS-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.

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