Journal
CELL STEM CELL
Volume 15, Issue 1, Pages 51-65Publisher
CELL PRESS
DOI: 10.1016/j.stem.2014.04.021
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Funding
- NHLBI [R01 HL068256, HL55716]
- ITRAC program at Indiana University Simon Cancer Center
- RSFG at IUPUI
- Indiana Center for Excellence in Molecular Hematology [NIDDK P30 DK090948]
- [R01 CA134777]
- Direct For Computer & Info Scie & Enginr
- Division of Computing and Communication Foundations [1217906] Funding Source: National Science Foundation
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The microRNA miR-155 has been implicated in regulating inflammatory responses and tumorigenesis, but its precise role in linking inflammation and cancer has remained elusive. Here, we identify a connection between miR-155 and Notch signaling in this context. Loss of Notch signaling in the bone marrow (BM) niche alters hematopoietic homeostasis and leads to lethal myeloproliferative-like disease. Mechanistically, Notch signaling represses miR-155 expression by promoting binding of RBPJ to the miR-155 promoter. Loss of Notch/RBPJ signaling upregulates miR-155 in BM endothelial cells, leading to miR-155-mediated targeting of the nuclear factor kappa B (NF-kappa B) inhibitor kappa B-Ras1, NF-kappa B activation, and increased proinflammatory cytokine production. Deletion of miR-155 in the stroma of RBPJ(-/-) mice prevented the development of myeloproliferative-like disease and cytokine induction. Analysis of BM from patients carrying myeloproliferative neoplasia also revealed elevated expression of miR-155. Thus, the Notch/miR-155/kappa B-Ras1/NF-kappa B axis regulates the inflammatory state of the BM niche and affects the development of myeloproliferative disorders.
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