Key result
Constitutive activation of the canonical NF-κB pathway in hematopoietic stem cells causes complete depletion of the HSC pool, pancytopenia, bone marrow failure, and premature death.
Constitutive activation of the canonical NF-κB pathway in hematopoietic stem cells causes bone marrow failure and premature death via Klf1-mediated suppression of c-Mpl.
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Suggests NF-κB hyperactivation drives HSC failure in mice; leaves open relevance to human bone marrow failure.
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.
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Nakagawa et al. (2018) studied Bone marrow failure. Constitutive activation of canonical NF-κB pathway (IKK2 activation) was evaluated on HSC pool depletion, pancytopenia, bone marrow failure, and premature death. Constitutive activation of the canonical NF-κB pathway in hematopoietic stem cells causes complete depletion of the HSC pool, pancytopenia, bone marrow failure, and premature death.
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