| First Author | Nakagawa MM | Year | 2018 |
| Journal | Cell Rep | Volume | 25 |
| Issue | 8 | Pages | 2094-2109.e4 |
| PubMed ID | 30463008 | Mgi Jnum | J:270706 |
| Mgi Id | MGI:6278648 | Doi | 10.1016/j.celrep.2018.10.071 |
| Citation | Nakagawa MM, et al. (2018) Constitutive Activation of the Canonical NF-kappaB Pathway Leads to Bone Marrow Failure and Induction of Erythroid Signature in Hematopoietic Stem Cells. Cell Rep 25(8):2094-2109.e4 |
| abstractText | Constitutive activation of the canonical NF-kappaB pathway has been associated with a variety of human pathologies. However, molecular mechanisms through which canonical NF-kappaB affects hematopoiesis remain elusive. Here, we demonstrate that deregulated canonical NF-kappaB 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-kappaB 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-kappaB. In essence, these studies identified a previously unknown mechanism through which exaggerated canonical NF-kappaB signals affect HSCs and cause pathophysiology. |
