TGF-? Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure
in Fanconi Anemia
#MMPMID27053300
Zhang H
; Kozono DE
; O'Connor KW
; Vidal-Cardenas S
; Rousseau A
; Hamilton A
; Moreau L
; Gaudiano EF
; Greenberger J
; Bagby G
; Soulier J
; Grompe M
; Parmar K
; D'Andrea AD
Cell Stem Cell
2016[May]; 18
(5
): 668-81
PMID27053300
show ga
Fanconi anemia (FA) is an inherited DNA repair disorder characterized by
progressive bone marrow failure (BMF) from hematopoietic stem and progenitor cell
(HSPC) attrition. A greater understanding of the pathogenesis of BMF could
improve the therapeutic options for FA patients. Using a genome-wide shRNA screen
in human FA fibroblasts, we identify transforming growth factor-? (TGF-?)
pathway-mediated growth suppression as a cause of BMF in FA. Blocking the TGF-?
pathway improves the survival of FA cells and rescues the proliferative and
functional defects of HSPCs derived from FA mice and FA patients. Inhibition of
TGF-? signaling in FA HSPCs results in elevated homologous recombination (HR)
repair with a concomitant decrease in non-homologous end-joining (NHEJ),
accounting for the improvement in cellular growth. Together, our results suggest
that elevated TGF-? signaling contributes to BMF in FA by impairing HSPC function
and may be a potential therapeutic target for the treatment of FA.
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