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

Nerea Berastegui, Marina Ainciburu, Juan P. Romero, Paula Garcia-Olloqui, Ana Alfonso-Pierola, Céline Philippe, Amaia Vilas-Zornoza, Patxi San Martin-Uriz, Raquel Ruiz-Hernández, Ander Abarrategi, Raquel Ordoñez, Diego Alignani, Sarai Sarvide, Laura Castro-Labrador, José M. Lamo-Espinosa, Mikel San-Julian, Tamara Jimenez, Félix López-Cadenas, Sandra Muntion, Fermin Sanchez-Guijo, Antonieta Molero, Maria Julia Montoro, Bárbara Tazón, Guillermo Serrano, Aintzane Diaz-Mazkiaran, Mikel Hernaez, Sofía Huerga, Findlay Bewicke-Copley, Ana Rio-Machin, Matthew T. Maurano, María Díez-Campelo, David Valcarcel, Kevin Rouault-Pierre, David Lara-Astiaso, Teresa Ezponda () and Felipe Prosper ()
Additional contact information
Nerea Berastegui: Instituto de Investigación Sanitaria de Navarra (IDISNA)
Marina Ainciburu: Instituto de Investigación Sanitaria de Navarra (IDISNA)
Juan P. Romero: Instituto de Investigación Sanitaria de Navarra (IDISNA)
Paula Garcia-Olloqui: Instituto de Investigación Sanitaria de Navarra (IDISNA)
Ana Alfonso-Pierola: Instituto de Salud Carlos III
Céline Philippe: Barts Cancer Institute, Queen Mary University of London
Amaia Vilas-Zornoza: Instituto de Investigación Sanitaria de Navarra (IDISNA)
Patxi San Martin-Uriz: Instituto de Investigación Sanitaria de Navarra (IDISNA)
Raquel Ruiz-Hernández: Basque Research and Technology Alliance (BRTA)
Ander Abarrategi: Basque Research and Technology Alliance (BRTA)
Raquel Ordoñez: NYU School of Medicine
Diego Alignani: Instituto de Investigación Sanitaria de Navarra (IDISNA)
Sarai Sarvide: Instituto de Investigación Sanitaria de Navarra (IDISNA)
Laura Castro-Labrador: Instituto de Investigación Sanitaria de Navarra (IDISNA)
José M. Lamo-Espinosa: Clínica Universidad de Navarra, Universidad de Navarra and CCUN
Mikel San-Julian: Clínica Universidad de Navarra, Universidad de Navarra and CCUN
Tamara Jimenez: Universidad de Salamanca
Félix López-Cadenas: Universidad de Salamanca
Sandra Muntion: Universidad de Salamanca
Fermin Sanchez-Guijo: Instituto de Salud Carlos III
Antonieta Molero: Hospital Universitari Vall d’Hebron
Maria Julia Montoro: Hospital Universitari Vall d’Hebron
Bárbara Tazón: Hospital Universitari Vall d’Hebron
Guillermo Serrano: Instituto de Investigación Sanitaria de Navarra (IDISNA)
Aintzane Diaz-Mazkiaran: Instituto de Investigación Sanitaria de Navarra (IDISNA)
Mikel Hernaez: Instituto de Salud Carlos III
Sofía Huerga: Clínica Universidad de Navarra, Universidad de Navarra and CCUN
Findlay Bewicke-Copley: Queen Mary University of London
Ana Rio-Machin: Queen Mary University of London
Matthew T. Maurano: NYU School of Medicine
María Díez-Campelo: Instituto de Salud Carlos III
David Valcarcel: Hospital Universitari Vall d’Hebron
Kevin Rouault-Pierre: Barts Cancer Institute, Queen Mary University of London
David Lara-Astiaso: Instituto de Investigación Sanitaria de Navarra (IDISNA)
Teresa Ezponda: Instituto de Investigación Sanitaria de Navarra (IDISNA)
Felipe Prosper: Instituto de Investigación Sanitaria de Navarra (IDISNA)

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35192-7

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DOI: 10.1038/s41467-022-35192-7

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