Ectopic HOXB4 overcomes the inhibitory effect of tumor necrosis factor-{alpha} on Fanconi anemia hematopoietic stem and progenitor cells.
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.
Milsom
Michael D
MD
Children's Hospital Boston and Harvard Stem Cell Institute, MA, USA.
Schiedlmeier
Bernhard
B
Bailey
Jeff
J
Kim
Mi-Ok
MO
Li
Dandan
D
Jansen
Michael
M
Ali
Abdullah Mahmood
AM
Kirby
Michelle
M
Baum
Christopher
C
Fairbairn
Leslie J
LJ
Williams
David A
DA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D005199:Fanconi Anemia / Q000473:pathology*; D052218:Fanconi Anemia Complementation Group C Protein / Q000172:deficiency; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D018398:Homeodomain Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis; D014157:Transcription Factors / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha