title: 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.
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Huajia
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Liyun
authors.initials: L
authors.lastname: Cao
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Parish
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Christen
authors.initials: C
authors.lastname: Mumaw
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Zollman
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Malgorzata M
authors.initials: MM
authors.lastname: Kamoka
authors.affiliation: Department of Computer Science and Engineering, University of Notre Dame, South Bend, IN 46556, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Mu
authors.affiliation: Department of Computer Science and Engineering, University of Notre Dame, South Bend, IN 46556, USA.
authors.forename: Danny Z
authors.initials: DZ
authors.lastname: Chen
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Srour
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Brahmananda R
authors.initials: BR
authors.lastname: Chitteti
authors.affiliation: Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Harm
authors.initials: H
authors.lastname: HogenEsch
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Tu
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Teresita M
authors.initials: TM
authors.lastname: Bellido
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: H Scott
authors.initials: HS
authors.lastname: Boswell
authors.affiliation: Leukemia Department, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Taghi
authors.initials: T
authors.lastname: Manshouri
authors.affiliation: Leukemia Department, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Mervin C
authors.initials: MC
authors.lastname: Yoder
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Cardoso
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: ncarless@iu.edu.
authors.forename: Nadia
authors.initials: N
authors.lastname: Carlesso
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000502:physiology*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D063185:Epigenetic Repression; D015972:Gene Expression Regulation, Neoplastic; D019337:Hematologic Neoplasms / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009196:Myeloproliferative Disorders / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D055153:Stem Cell Niche; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D018836:Inflammation Mediators; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D016328:NF-kappa B; C497571:Rbpj protein, mouse; D051880:Receptors, Notch