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

Author

Listed:
  • Nerea Berastegui

    (Instituto de Investigación Sanitaria de Navarra (IDISNA)
    Instituto de Salud Carlos III)

  • Marina Ainciburu

    (Instituto de Investigación Sanitaria de Navarra (IDISNA)
    Instituto de Salud Carlos III)

  • Juan P. Romero

    (Instituto de Investigación Sanitaria de Navarra (IDISNA)
    Instituto de Salud Carlos III)

  • Paula Garcia-Olloqui

    (Instituto de Investigación Sanitaria de Navarra (IDISNA)
    Instituto de Salud Carlos III)

  • Ana Alfonso-Pierola

    (Instituto de Salud Carlos III
    Clínica Universidad de Navarra, Universidad de Navarra and CCUN)

  • Céline Philippe

    (Barts Cancer Institute, Queen Mary University of London)

  • Amaia Vilas-Zornoza

    (Instituto de Investigación Sanitaria de Navarra (IDISNA)
    Instituto de Salud Carlos III)

  • 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)
    Ikerbasque, Basque Foundation for Science)

  • Raquel Ordoñez

    (NYU School of Medicine)

  • Diego Alignani

    (Instituto de Investigación Sanitaria de Navarra (IDISNA)
    Instituto de Salud Carlos III)

  • Sarai Sarvide

    (Instituto de Investigación Sanitaria de Navarra (IDISNA)
    Instituto de Salud Carlos III)

  • Laura Castro-Labrador

    (Instituto de Investigación Sanitaria de Navarra (IDISNA)
    Instituto de Salud Carlos III)

  • 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
    Universidad de Salamanca)

  • 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)
    Instituto de Investigación Sanitaria de Navarra (IDISNA))

  • Mikel Hernaez

    (Instituto de Salud Carlos III
    Instituto de Investigación Sanitaria de Navarra (IDISNA))

  • 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
    NYU School of Medicine)

  • María Díez-Campelo

    (Instituto de Salud Carlos III
    Universidad de Salamanca)

  • 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)
    Instituto de Salud Carlos III)

  • Felipe Prosper

    (Instituto de Investigación Sanitaria de Navarra (IDISNA)
    Instituto de Salud Carlos III
    Clínica Universidad de Navarra, Universidad de Navarra and CCUN)

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.

Suggested Citation

  • 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 Abarra, 2022. "The transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35192-7
    DOI: 10.1038/s41467-022-35192-7
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    References listed on IDEAS

    as
    1. Moritz Gerstung & Andrea Pellagatti & Luca Malcovati & Aristoteles Giagounidis & Matteo G Della Porta & Martin Jädersten & Hamid Dolatshad & Amit Verma & Nicholas C. P. Cross & Paresh Vyas & Sally Kil, 2015. "Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes," Nature Communications, Nature, vol. 6(1), pages 1-11, May.
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    Cited by:

    1. Guillermo Serrano & Nerea Berastegui & Aintzane Díaz-Mazkiaran & Paula García-Olloqui & Carmen Rodriguez-Res & Sofia Huerga-Dominguez & Marina Ainciburu & Amaia Vilas-Zornoza & Patxi San Martin-Uriz &, 2024. "Single-cell transcriptional profile of CD34+ hematopoietic progenitor cells from del(5q) myelodysplastic syndromes and impact of lenalidomide," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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