The Role of HoxB4 in Hematopoiesis

Sammanfattning: HOXB4 is one of 39 members of the homeobox (HOX) family, a family of transcription factors involved in embryonic development. Several HOX transcription factors, including HOXB4, are highly expressed in hematopoietic stem cells (HSCs) but are downregulated upon differentiation towards more mature progeny cells. Enforced expression of HOXB4 dramatically increases the regeneration of murine HSC following transplantation, and enhances the repopulating ability of human SCID repopulating cells. In this thesis, the role of HOXB4 in hematopoiesis is explored through gain-of-function and lack-of-function approaches. Adenoviral mediated overexpression of HOXB4 in human primitive hematopoietic cells in vitro generates very high levels of HOXB4 within 24 hours of transduction, leading to an increased differentiation towards myeloid lineages, and to a reduction of primitive hematopoietic progenitors, suggesting that the level of HOXB4 expression may determine the fate options following gene transfer. Studies in our knockout mice reveal that deficiency of HOXB4 leads to a hypocellularity in hematopoietic organs and impaired proliferative capacity. However, HOXB4 is not required for generation of HSC or maintenance of steady state hematopoiesis. Collectively, these findings indicate that correct expression levels of HOXB4 improve proliferative recruitment of HSC in settings demanding high proliferation, for example after bone marrow transplantation. However, HoxB4 seems to have a less prominent role in normal endogenous hematopoiesis.