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

Academic Article

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.
  • Authors

    Published In

  • Cell Stem Cell  Journal
  • Keywords

  • Animals, Bone Marrow, Cell Line, Cytokines, Epigenetic Repression, Gene Expression Regulation, Neoplastic, Hematologic Neoplasms, Hematopoiesis, Humans, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Inflammation Mediators, Mice, Mice, Knockout, MicroRNAs, Myeloproliferative Disorders, NF-kappa B, Receptors, Notch, Signal Transduction, Stem Cell Niche, Up-Regulation
  • Digital Object Identifier (doi)

    Author List

  • Wang L; Zhang H; Rodriguez S; Cao L; Parish J; Mumaw C; Zollman A; Kamoka MM; Mu J; Chen DZ
  • Start Page

  • 51
  • End Page

  • 65
  • Volume

  • 15
  • Issue

  • 1