Ectopic HOXB4 overcomes the inhibitory effect of tumor necrosis factor-{alpha} on Fanconi anemia hematopoietic stem and progenitor cells.

2.50
Hdl Handle:
http://hdl.handle.net/10541/87571
Title:
Ectopic HOXB4 overcomes the inhibitory effect of tumor necrosis factor-{alpha} on Fanconi anemia hematopoietic stem and progenitor cells.
Authors:
Milsom, Michael D; Schiedlmeier, Bernhard; Bailey, Jeff; Kim, Mi-Ok; Li, Dandan; Jansen, Michael; Ali, Abdullah Mahmood; Kirby, Michelle; Baum, Christopher; Fairbairn, Leslie J; Williams, David A
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.
Affiliation:
Children's Hospital Boston and Harvard Stem Cell Institute, MA, USA.
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
Journal:
Blood
Issue Date:
21-May-2009
URI:
http://hdl.handle.net/10541/87571
DOI:
10.1182/blood-2008-09-180224
PubMed ID:
19270262
Type:
Article
Language:
en
ISSN:
1528-0020
Appears in Collections:
All Paterson Institute for Cancer Research; Biological Immune and Gene Therapy Group

Full metadata record

DC FieldValue Language
dc.contributor.authorMilsom, Michael Den
dc.contributor.authorSchiedlmeier, Bernharden
dc.contributor.authorBailey, Jeffen
dc.contributor.authorKim, Mi-Oken
dc.contributor.authorLi, Dandanen
dc.contributor.authorJansen, Michaelen
dc.contributor.authorAli, Abdullah Mahmooden
dc.contributor.authorKirby, Michelleen
dc.contributor.authorBaum, Christopheren
dc.contributor.authorFairbairn, Leslie Jen
dc.contributor.authorWilliams, David Aen
dc.date.accessioned2009-12-08T12:36:01Z-
dc.date.available2009-12-08T12:36:01Z-
dc.date.issued2009-05-21-
dc.identifier.citationEctopic HOXB4 overcomes the inhibitory effect of tumor necrosis factor-{alpha} on Fanconi anemia hematopoietic stem and progenitor cells. 2009, 113 (21):5111-20 Blooden
dc.identifier.issn1528-0020-
dc.identifier.pmid19270262-
dc.identifier.doi10.1182/blood-2008-09-180224-
dc.identifier.urihttp://hdl.handle.net/10541/87571-
dc.description.abstractEctopic 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.en
dc.language.isoenen
dc.subjectFanconi Anaemiaen
dc.subjectFanconi Anaemia Complementation Group C Proteinen
dc.subjectHaematopoietic Stem Cellsen
dc.subjectHaematopoietic Stem Cell Transplantationen
dc.subjectTumour Necrosis Factor-alphaen
dc.subject.meshAnimals-
dc.subject.meshApoptosis-
dc.subject.meshFanconi Anemia-
dc.subject.meshFanconi Anemia Complementation Group C Protein-
dc.subject.meshGraft Survival-
dc.subject.meshHematopoietic Stem Cell Transplantation-
dc.subject.meshHematopoietic Stem Cells-
dc.subject.meshHomeodomain Proteins-
dc.subject.meshMice-
dc.subject.meshMice, Knockout-
dc.subject.meshReactive Oxygen Species-
dc.subject.meshReceptors, Tumor Necrosis Factor-
dc.subject.meshTranscription Factors-
dc.subject.meshTumor Necrosis Factor-alpha-
dc.titleEctopic HOXB4 overcomes the inhibitory effect of tumor necrosis factor-{alpha} on Fanconi anemia hematopoietic stem and progenitor cells.en
dc.typeArticleen
dc.contributor.departmentChildren's Hospital Boston and Harvard Stem Cell Institute, MA, USA.en
dc.identifier.journalBlooden

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