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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2018Journal
Cell ReportsPublisher
Elsevier B.V.Type
Article
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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. ©2018Sponsors
This work was supported by a grant from the National Heart, Lung, and Blood Institute (NHLBI) ( HL132194 , to C.V.R.).Keyword
bone marrow failureerythroid differentiation
NF-kB
self-renewal
Hematopoietic Stem Cells
Pancytopenia
Signal Transduction
Transcription Factors
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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/10713/8771ae974a485f413a2113503eed53cd6c53
10.1016/j.celrep.2018.10.071
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