| First Author | Du W | Year | 2013 |
| Journal | J Immunol | Volume | 191 |
| Issue | 5 | Pages | 2806-17 |
| PubMed ID | 23926327 | Mgi Jnum | J:205786 |
| Mgi Id | MGI:5546453 | Doi | 10.4049/jimmunol.1203474 |
| Citation | Du W, et al. (2013) Inflammation-mediated notch signaling skews fanconi anemia hematopoietic stem cell differentiation. J Immunol 191(5):2806-17 |
| abstractText | Hematopoietic stem cells (HSCs) can either self-renew or differentiate into various types of cells of the blood lineage. Signaling pathways that regulate this choice of self-renewal versus differentiation are currently under extensive investigation. In this study, we report that deregulation of Notch signaling skews HSC differentiation in mouse models of Fanconi anemia (FA), a genetic disorder associated with bone marrow failure and progression to leukemia and other cancers. In mice expressing a transgenic Notch reporter, deletion of the Fanca or Fancc gene enhances Notch signaling in multipotential progenitors (MPPs), which is correlated with decreased phenotypic long-term HSCs and increased formation of MPP1 progenitors. Furthermore, we found an inverse correlation between Notch signaling and self-renewal capacity in FA hematopoietic stem and progenitor cells. Significantly, FA deficiency in MPPs deregulates a complex network of genes in the Notch and canonical NF-kappaB pathways. Genetic ablation or pharmacologic inhibition of NF-kappaB reduces Notch signaling in FA MPPs to near wild type level, and blocking either NF-kappaB or Notch signaling partially restores FA HSC quiescence and self-renewal capacity. These results suggest a functional crosstalk between Notch signaling and NF-kappaB pathway in regulation of HSC differentiation. |
