Ectopic HOXB4 overcomes the inhibitory effect of tumor necrosis factor-{alpha} on Fanconi anemia hematopoietic stem and progenitor cells.
Milsom, Michael D Schiedlmeier, Bernhard Bailey, Jeff Kim, Mi-Ok Li, Dandan Jansen, Michael Ali, Abdullah Mahmood Kirby, Michelle Baum, Christopher Fairbairn, Leslie J
Milsom, Michael D
Schiedlmeier, Bernhard
Bailey, Jeff
Kim, Mi-Ok
Li, Dandan
Jansen, Michael
Ali, Abdullah Mahmood
Kirby, Michelle
Baum, Christopher
Fairbairn, Leslie J
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Abstract
Ectopic delivery of HOXB4 elicits the expansion of engrafting hematopoietic stem cells (HSCs). We hypothesized that inhibition of tumor necrosis factor-alpha (TNF-alpha) signaling may be central to the self-renewal signature of HOXB4. Because HSCs derived from Fanconi anemia (FA) knockout mice are hypersensitive to TNF-alpha, we studied Fancc(-/-) HSCs to determine the physiologic effects of HOXB4 on TNF-alpha sensitivity and the relationship of these effects to the engraftment defect of FA HSCs. Overexpression of HOXB4 reversed the in vitro hypersensitivity to TNF-alpha of Fancc(-/-) HSCs and progenitors (P) and partially rescued the engraftment defect of these cells. Coexpression of HOXB4 and the correcting FA-C protein resulted in full correction compared with wild-type (WT) HSCs. Ectopic expression of HOXB4 resulted in a reduction in both apoptosis and reactive oxygen species in Fancc(-/-) but not WT HSC/P. HOXB4 overexpression was also associated with a significant reduction in surface expression of TNF-alpha receptors on Fancc(-/-) HSC/P. Finally, enhanced engraftment was seen even when HOXB4 was expressed in a time-limited fashion during in vivo reconstitution. Thus, the HOXB4 engraftment signature may be related to its effects on TNF-alpha signaling, and this pathway may be a molecular target for timed pharmacologic manipulation of HSC during reconstitution.
Description
Date
2009-05-21
Publisher
Keywords
Fanconi Anaemia
Fanconi Anaemia Complementation Group C Protein
Haematopoietic Stem Cells
Haematopoietic Stem Cell Transplantation
Tumour Necrosis Factor-alpha
Fanconi Anaemia Complementation Group C Protein
Haematopoietic Stem Cells
Haematopoietic Stem Cell Transplantation
Tumour Necrosis Factor-alpha
Type
Article
Citation
Ectopic HOXB4 overcomes the inhibitory effect of tumor necrosis factor-{alpha} on Fanconi anemia hematopoietic stem and progenitor cells. 2009, 113 (21):5111-20 Blood