نبذة مختصرة : 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.
Relation: Nature Communications; Kreftforeningen: 6765150; Norges forskningsråd: 250901; Norges forskningsråd: 247596; UiT Norges arktiske universitet: Strategisk-HN06-14; Regionalt helseforetak: HNF1338-17; Villatoro AE, Cuminetti V, Bernal A, Torroja, Cossío, Benguría, Ferré, Konieczny J, Vázquez, Rubio, Utnes PA, You, Fenton CG, Paulssen RH, Zhang J, Sánchez-Cabo, Dopazo, Vik A, Anderssen E, Hidalgo, Arranz L. Endogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation. Nature Communications. 2023;14; FRIDAID 2102650; https://hdl.handle.net/10037/30158
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