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Endogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation

Author

Listed:
  • Alicia Villatoro

    (UiT – The Arctic University of Norway)

  • Vincent Cuminetti

    (UiT – The Arctic University of Norway)

  • Aurora Bernal

    (UiT – The Arctic University of Norway)

  • Carlos Torroja

    (Bioinformatics Unit, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC))

  • Itziar Cossío

    (Area of Cell and Developmental Biology, CNIC)

  • Alberto Benguría

    (Genomics Unit, CNIC)

  • Marc Ferré

    (UiT – The Arctic University of Norway)

  • Joanna Konieczny

    (UiT – The Arctic University of Norway)

  • Enrique Vázquez

    (Genomics Unit, CNIC)

  • Andrea Rubio

    (Area of Cell and Developmental Biology, CNIC)

  • Peter Utnes

    (UiT – The Arctic University of Norway)

  • Almudena Tello

    (UiT – The Arctic University of Norway)

  • Xiaona You

    (University of Wisconsin-Madison)

  • Christopher G. Fenton

    (UiT – The Arctic University of Norway)

  • Ruth H. Paulssen

    (UiT – The Arctic University of Norway
    UiT – The Arctic University of Norway)

  • Jing Zhang

    (University of Wisconsin-Madison)

  • Fátima Sánchez-Cabo

    (Bioinformatics Unit, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC))

  • Ana Dopazo

    (Genomics Unit, CNIC)

  • Anders Vik

    (University Hospital of North Norway)

  • Endre Anderssen

    (UiT – The Arctic University of Norway)

  • Andrés Hidalgo

    (Area of Cell and Developmental Biology, CNIC)

  • Lorena Arranz

    (UiT – The Arctic University of Norway
    University of Oslo)

Abstract

Here we explored the role of interleukin-1β (IL-1β) repressor cytokine, IL-1 receptor antagonist (IL-1rn), in both healthy and abnormal hematopoiesis. Low IL-1RN is frequent in acute myeloid leukemia (AML) patients and represents a prognostic marker of reduced survival. Treatments with IL-1RN and the IL-1β monoclonal antibody canakinumab reduce the expansion of leukemic cells, including CD34+ progenitors, in AML xenografts. In vivo deletion of IL-1rn induces hematopoietic stem cell (HSC) differentiation into the myeloid lineage and hampers B cell development via transcriptional activation of myeloid differentiation pathways dependent on NFκB. Low IL-1rn is present in an experimental model of pre-leukemic myelopoiesis, and IL-1rn deletion promotes myeloproliferation, which relies on the bone marrow hematopoietic and stromal compartments. Conversely, IL-1rn protects against pre-leukemic myelopoiesis. Our data reveal that HSC differentiation is controlled by balanced IL-1β/IL-1rn levels under steady-state, and that loss of repression of IL-1β signaling may underlie pre-leukemic lesion and AML progression.

Suggested Citation

  • Alicia Villatoro & Vincent Cuminetti & Aurora Bernal & Carlos Torroja & Itziar Cossío & Alberto Benguría & Marc Ferré & Joanna Konieczny & Enrique Vázquez & Andrea Rubio & Peter Utnes & Almudena Tello, 2023. "Endogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation," Nature Communications, Nature, vol. 14(1), pages 1-28, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35700-9
    DOI: 10.1038/s41467-022-35700-9
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