Endogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation
AuthorVillatoro, Alicia; Cuminetti, Vincent; Bernal, Aurora; Torroja, Carlos; Cossío, Itziar; Benguría, Alberto; Ferré, Marc; Konieczny, Joanna; Vázquez, Enrique; Rubio, Andrea; Utnes, Peter Andree; You, Xiaona; Fenton, Christopher Graham; Paulssen, Ruth H; Zhang, Jing; Sánchez-Cabo, Fatima; Dopazo, Ana; Vik, Anders; Anderssen, Endre; Hidalgo, Andres; Arranz, Lorena
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.