Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-κB-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 κB (NF-κB) inhibitor κB-Ras1, NF-κB 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/κB-Ras1/NF-κB axis regulates the inflammatory state of the BM niche and affects the development of myeloproliferative disorders.

DOI: 10.1016/j.stem.2014.04.021

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@article{Wang2014NotchdependentRO, title={Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-κB-dependent manner.}, author={Lin Wang and Huajia Zhang and Sonia I Rodriguez and Liyun Y Cao and Jonathan Parish and Christen L Mumaw and Amy L. Zollman and Malgorzata M Kamoka and Jian Mu and Danny Ziyi Chen and Edward F. Srour and Brahmananda Chitteti and Harm HogenEsch and Xiaolin Tu and Teresita M. Bellido and H . Scott Boswell and Taghi Manshouri and Srdan Verstovsek and Mervin C. Yoder and Reuben Kapur and Angelo Almeida Cardoso and Nadia Carlesso}, journal={Cell stem cell}, year={2014}, volume={15 1}, pages={51-65} }