Endogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation

Alicia Villatoro, Vincent Cuminetti, Aurora Bernal, Carlos Torroja, Itziar Cossío, Alberto Benguría, Marc Ferré, Joanna Konieczny, Enrique Vázquez, Andrea Rubio, Peter Utnes, Almudena Tello, Xiaona You, Christopher G. Fenton, Ruth H. Paulssen, Jing Zhang, Fátima Sánchez-Cabo, Ana Dopazo, Anders Vik, Endre Anderssen, Andrés Hidalgo and Lorena Arranz ()
Additional contact information
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
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

Nature Communications, 2023, vol. 14, issue 1, 1-28

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-022-35700-9

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