Endogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation

Nature Communications

Article

Andrés Hidalgo¹  Itziar Cossío¹  Andrea Rubio¹  Carlos Torroja²  Fátima Sánchez-Cabo²  Anders Vik³  Endre Anderssen⁴  Christopher G. Fenton⁴  Ruth H. Paulssen⁵  Enrique Vázquez⁶  Alberto Benguría⁶  Ana Dopazo⁶  Jing Zhang⁷  Xiaona You⁷  Peter Utnes⁸  Alicia Villatoro⁸  Vincent Cuminetti⁸  Almudena Tello⁸  Joanna Konieczny⁸  Marc Ferré⁸  Aurora Bernal⁸  Lorena Arranz⁹ 

[1] Area of Cell and Developmental Biology, CNIC, 28029, Madrid, Spain;Bioinformatics Unit, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029, Madrid, Spain;Department of Hematology, University Hospital of North Norway, 9019, Tromsø, Norway;Genomics Support Center Tromsø, Faculty of Health Sciences, UiT – The Arctic University of Norway, MH building level 9, 9019, Tromsø, Norway;Genomics Support Center Tromsø, Faculty of Health Sciences, UiT – The Arctic University of Norway, MH building level 9, 9019, Tromsø, Norway;Clinical Bioinformatics Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT – The Arctic University of Norway, MH building level 9, 9019, Tromsø, Norway;Genomics Unit, CNIC, 28029, Madrid, Spain;McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, 53705, Madison, WI, USA;Stem Cells, Ageing and Cancer Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of Norway, MH2 building level 10, 9019, Tromsø, Norway;Stem Cells, Ageing and Cancer Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of Norway, MH2 building level 10, 9019, Tromsø, Norway;Associate Investigator, Norwegian Center for Molecular Medicine (NCMM), University of Oslo, 0349, Oslo, Norway;

关键词: ;   

DOI  :  10.1038/s41467-022-35700-9

 received in 2021-06-24, accepted in 2022-12-16,  发布年份 2022

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2023. corrected publication 2023

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