dc.description.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. | es_ES |
dc.description.sponsorship | We thank K. Tasken, J. Saarela and the NCMM at the University of
Oslo (UiO), S. Kanse (UiO) and B. Smedsrød (UiT), for access to
facilities. We acknowledge Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital (Bergen, Norway)
and R. Hovland for karyotyping, FISH, translocation and DNA analyses of AML and MDS patients included in this study, and
Department of Pathology, Oslo University Hospital (Oslo, Norway)
and S. Spetalen for deep sequencing. L.M. Gonzalez, L.T. Eliassen,
X. Zhang, M. Ristic and other members of L. Arranz group, O.P.
Rekvig, R. Doohan, L.D. Håland, M.I. Olsen, A. Urbanucci, J. Landskron, K.B. Larsen, R.A. Lyså and UiT Advanced Microscopy Core
Facility, UiO and UiT Comparative Medicine Units, for assistance.
P. Garcia and S. Mendez-Ferrer for providing NRASG12D and Nes-gfp
mice, respectively. P. Garcia and L. Kurian for careful reading of the manuscript. E. Tenstad (Science Shaped) for artwork in schematics.
We would also like to thank the AML and MDS patients, and healthy
volunteers, who donated biological samples. Our work is supported by a joint meeting grant of the Northern Norway Regional
Health Authority, the University Hospital of Northern Norway (UNN)
and UiT (Strategisk-HN06-14), Young Research Talent grants from
the Research Council of Norway, (Stem Cell Program, 247596;
FRIPRO Program, 250901), and grants from the Norwegian Cancer
Society (6765150), the Northern Norway Regional Health Authority
(HNF1338-17), and the Aakre-Stiftelsen Foundation (2016/9050) to
L.A. Vav-Cre NRASG12D experiments were supported by NIH grant
R01CA152108 to J.Z. | es_ES |