title: TGF-β Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia.
abstract: 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-β (TGF-β) pathway-mediated growth suppression as a cause of BMF in FA. Blocking the TGF-β 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-β 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-β signaling contributes to BMF in FA by impairing HSPC function and may be a potential therapeutic target for the treatment of FA.
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Haojian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Kozono
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: O'Connor
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Vidal-Cardenas
authors.affiliation: Institute of Hematology (IUH), University Paris-Diderot, 75010 Paris, France.
authors.forename: Alix
authors.initials: A
authors.lastname: Rousseau
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Hamilton
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Moreau
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Emily F
authors.initials: EF
authors.lastname: Gaudiano
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Greenberger
authors.affiliation: Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Grover
authors.initials: G
authors.lastname: Bagby
authors.affiliation: Institute of Hematology (IUH), University Paris-Diderot, 75010 Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.affiliation: Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Kalindi
authors.initials: K
authors.lastname: Parmar
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: alan_dandrea@dfci.harvard.edu.
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
mesh_terms: D000079:Acetaldehyde / Q000633:toxicity; D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D059766:DNA End-Joining Repair / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005199:Fanconi Anemia / Q000473:pathology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D009153:Mutagens; D016212:Transforming Growth Factor beta; D000079:Acetaldehyde