Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-?B-dependent manner.

ABSTRACT: 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 ?B (NF-?B) inhibitor ?B-Ras1, NF-?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/?B-Ras1/NF-?B axis regulates the inflammatory state of the BM niche and affects the development of myeloproliferative disorders.

SUBMITTER: Wang L 

PROVIDER: S-EPMC4398997 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature