Endogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation

Enhanced IL-1 beta signaling pathway causes hematopoietic stem cell (HSC) to differentiate into myeloid cells and contributes to malignant hematopoiesis. Here the authors reveal that HSC differentiation is controlled by balanced levels of IL-1 receptor antagonist (IL-1rn) and IL-1 beta under steady-state, and that IL-1rn protects against pre-leukemic myelopoiesis by repressing IL-1 beta signaling. Here we explored the role of interleukin-1 beta (IL-1 beta) 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-1 beta 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 NF kappa B. 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-1 beta/IL-1rn levels under steady-state, and that loss of repression of IL-1 beta signaling may underlie pre-leukemic lesion and AML progression.

Automated summary

The balance between IL-1rn and IL-1 beta levels regulates HSC differentiation, and repression of IL-1 beta signaling by IL-1rn protects against pre-leukemic myelopoiesis.