Scientific publications
The transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes
Nerea Berastegui # 1 2 , Marina Ainciburu # 1 2 , Juan P Romero 1 2 , Paula Garcia-Olloqui 1 2 , Ana Alfonso-Pierola 2 3 , Céline Philippe 4 , Amaia Vilas-Zornoza 1 2 , Patxi San Martin-Uriz 1 , Raquel Ruiz-Hernández 5 , Ander Abarrategi 5 6 , Raquel Ordoñez 7 , Diego Alignani 1 2 , Sarai Sarvide 1 2 , Laura Castro-Labrador 1 2 , José M Lamo-Espinosa 8 , Mikel San-Julian 8 , Tamara Jimenez 9 , Félix López-Cadenas 9 , Sandra Muntion 9 , Fermin Sanchez-Guijo 2 9 , Antonieta Molero 10 , Maria Julia Montoro 10 , Bárbara Tazón 10 , Guillermo Serrano 11 , Aintzane Diaz-Mazkiaran 1 11 , Mikel Hernaez 2 11 , Sofía Huerga 3 , Findlay Bewicke-Copley 12 , Ana Rio-Machin 12 , Matthew T Maurano 7 13 , María Díez-Campelo 2 9 , David Valcarcel 10 , Kevin Rouault-Pierre 4 , David Lara-Astiaso 1 , Teresa Ezponda # 14 15 , Felipe Prosper # 16 17 18
Abstract
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.
CITATION Nat Commun. 2022 Dec 9;13(1):7619. doi: 10.1038/s41467-022-35192-7
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