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

In Nature communications ; h5-index 260.0

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.

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-Espinosa José M, San-Julian Mikel, Jimenez Tamara, López-Cadenas Félix, Muntion Sandra, Sanchez-Guijo Fermin, Molero Antonieta, Montoro Maria Julia, Tazón Bárbara, Serrano Guillermo, Diaz-Mazkiaran Aintzane, Hernaez Mikel, Huerga Sofía, Bewicke-Copley Findlay, Rio-Machin Ana, Maurano Matthew T, Díez-Campelo María, Valcarcel David, Rouault-Pierre Kevin, Lara-Astiaso David, Ezponda Teresa, Prosper Felipe

2022-Dec-09