Show simple item record

dc.contributor.authorNakagawa, M.M.
dc.contributor.authorRathinam, C.V.
dc.date.accessioned2019-04-05T13:55:09Z
dc.date.available2019-04-05T13:55:09Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85056712351&doi=10.1016%2fj.celrep.2018.10.071&partnerID=40&md5=d5804ad3832d3db7dfee014311a5d96d
dc.identifier.urihttp://hdl.handle.net/10713/8771
dc.description.abstractConstitutive activation of the canonical NF-κB pathway has been associated with a variety of human pathologies. However, molecular mechanisms through which canonical NF-κB affects hematopoiesis remain elusive. Here, we demonstrate that deregulated canonical NF-κB signals in hematopoietic stem cells (HSCs) cause a complete depletion of HSC pool, pancytopenia, bone marrow failure, and premature death. Constitutive activation of IKK2 in HSCs leads to impaired quiescence and loss of function. Gene set enrichment analysis (GSEA) identified an induction of "erythroid signature" in HSCs with augmented NF-κB activity. Mechanistic studies indicated a reduction of thrombopoietin (TPO)-mediated signals and its downstream target p57 in HSCs, due to reduced c-Mpl expression in a cell-intrinsic manner. Molecular studies established Klf1 as a key suppressor of c-Mpl in HSPCs with increased NF-κB. In essence, these studies identified a previously unknown mechanism through which exaggerated canonical NF-κB signals affect HSCs and cause pathophysiology. Nakagawa and Rathinam demonstrate that constitutive activation of IKK2 in HSCs causes a complete depletion of the HSC pool and impairs HSC functions due to a loss of "stemness" signature and an induction of erythroid signature. ©2018en_US
dc.description.sponsorshipThis work was supported by a grant from the National Heart, Lung, and Blood Institute (NHLBI) ( HL132194 , to C.V.R.).en_US
dc.description.urihttps://dx.doi.org/10.1016/j.celrep.2018.10.071en_US
dc.language.isoEnglishen_US
dc.publisherElsevier B.V.en_US
dc.relation.ispartofCell Reports
dc.subjectbone marrow failureen_US
dc.subjecterythroid differentiationen_US
dc.subjectNF-kBen_US
dc.subjectself-renewalen_US
dc.subject.meshHematopoietic Stem Cellsen_US
dc.subject.meshPancytopeniaen_US
dc.subject.meshSignal Transductionen_US
dc.subject.meshTranscription Factorsen_US
dc.titleConstitutive Activation of the Canonical NF-kB Pathway Leads to Bone Marrow Failure and Induction of Erythroid Signature in Hematopoietic Stem Cellsen_US
dc.typeArticleen_US
dc.identifier.doi10.1016/j.celrep.2018.10.071
dc.identifier.pmid30463008


Files in this item

Thumbnail
Name:
Publisher version

This item appears in the following Collection(s)

Show simple item record