Scientific publications

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

Dec 9, 2022 | Magazine: Nature Communications

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

Our authors

Nerea Berastegui Zufiaurre
Investigadora predoctoral del Grupo de Patología Mieloide del Cima Universidad de Navarra
Marina Ainciburu Fernández
Dr. Teresa Ezponda Itoiz
Investigador postdoctoral del Grupo de Patología Mieloide del Cima Universidad de Navarra
Juan Pablo Romero Riojas
Dr. Paula García Olloqui
Dr. Patxi San Martín Uriz
Diego Alignani
Laboratory technician Cytometry Platform
Guillermo Serrano Sanz
Bioinformatics Research Technician Computational Biology Program
Dr. Mikel
Director | Principal Investigator Bioinformatics Platform