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    Constitutive Activation of the Canonical NF-kB Pathway Leads to Bone Marrow Failure and Induction of Erythroid Signature in Hematopoietic Stem Cells

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    Author
    Nakagawa, M.M.
    Rathinam, C.V.
    Date
    2018
    Journal
    Cell Reports
    Publisher
    Elsevier B.V.
    Type
    Article
    
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    See at
    https://dx.doi.org/10.1016/j.celrep.2018.10.071
    Abstract
    Constitutive 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. ©2018
    Sponsors
    This work was supported by a grant from the National Heart, Lung, and Blood Institute (NHLBI) ( HL132194 , to C.V.R.).
    Keyword
    bone marrow failure
    erythroid differentiation
    NF-kB
    self-renewal
    Hematopoietic Stem Cells
    Pancytopenia
    Signal Transduction
    Transcription Factors
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85056712351&doi=10.1016%2fj.celrep.2018.10.071&partnerID=40&md5=d5804ad3832d3db7dfee014311a5d96d; http://hdl.handle.net/10713/8771
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.celrep.2018.10.071
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    UMB Open Access Articles 2018

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