Inflammation-mediated notch signaling skews fanconi anemia hematopoietic stem cell differentiation.
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-κB pathways. Genetic ablation or pharmacologic inhibition of NF-κB reduces Notch signaling in FA MPPs to near wild type level, and blocking either NF-κB or Notch signaling partially restores FA HSC quiescence and self-renewal capacity. These results suggest a functional crosstalk between Notch signaling and NF-κB pathway in regulation of HSC differentiation.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Wei
W
Du
Surya
S
Amarachintha
Jared
J
Sipple
Jonathan
J
Schick
Kris
K
Steinbrecher
Qishen
Q
Pang
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D004195:Disease Models, Animal; D005199:Fanconi Anemia / Q000378:metabolism*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D015151:Immunoblotting; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000502:physiology; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D016328:NF-kappa B; D051880:Receptors, Notch