Nuclear Factor \(\kappa\)B transcriptional regulator function in haemopoietic stem cells

Sheriff, Lozan (2012). Nuclear Factor \(\kappa\)B transcriptional regulator function in haemopoietic stem cells. University of Birmingham. Ph.D.

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The NF-\(\kappa\)B family of transcription factors are essential for different stages of murine haemopoiesis as supported by studies on single or double knockout mice. The function of NF-\(\kappa\)B1 and NF-\(\kappa\)B2 in haemopoietic stem cells (HSCs) has never been described before. In mice, the bone marrow c-Kit+Sca1+Lin- (KSL) population represent HSCs that have the ability to repopulate the bone marrow of lethally irradiated animals. Using knockout mice technology we were able to study the function of NF-\(\kappa\)B1 and NF-\(\kappa\)B2 in HSCs by performing amongst others transplantation assays, which is the most precise way to test HSC potential. Nf\(\kappa\)b1-/- KSL cells are fully able to reconstitute lethally irradiated recipients indicating that the in vivo self-renewal capacity is unaffected. In contrast, colony assays showed NF-\(\kappa\)B1 dependency. Upon serial replating, knockout cells were not able to form colonies and lost their in vitro self-renewal capacity. Transplantation of the nf\(\kappa\)b2-/- KSL cells engraft with a proliferative phenotype and a competitive advantage, with changes in the B-cell and myeloid cell lineages. Similar to nf\(\kappa\)b1-/-, nf\(\kappa\)b2-/- KSL cells lose their function as stem cells upon serial replating. These findings highlight the importance of NF-\(\kappa\)B family proteins in HSCs, especially NF-\(\kappa\)B2 and should be considered in the development of future cancer treatment that target NF-B proteins.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: School of Immunity and Infection
Funders: Medical Research Council
Subjects: R Medicine > RK Dentistry


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