TGF-β inhibition rescues hematopoietic stem cell defects and bone marrow failure in Fanconi anemia

Haojian Zhang; David E. Kozono; Kevin W. O'Connor; Sofia Vidal-Cardenas; Alix Rousseau; Abigail Hamilton; Lisa Moreau; Emily F. Gaudiano; Joel Greenberger; Grover Bagby; Jean Soulier; Markus Grompe; Kalindi Parmar; Alan D. D'Andrea

doi:10.1016/j.stem.2016.03.002

TGF-β inhibition rescues hematopoietic stem cell defects and bone marrow failure in Fanconi anemia

Haojian Zhang, David E. Kozono, Kevin W. O'Connor, Sofia Vidal-Cardenas, Alix Rousseau, Abigail Hamilton, Lisa Moreau, Emily F. Gaudiano, Joel Greenberger, Grover Bagby, Jean Soulier, Markus Grompe, Kalindi Parmar, Alan D. D'Andrea

Research output: Contribution to journal › Article › peer-review

127 Scopus citations

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.

Original language	English (US)
Pages (from-to)	668-681
Number of pages	14
Journal	Cell Stem Cell
Volume	18
Issue number	5
DOIs	https://doi.org/10.1016/j.stem.2016.03.002
State	Published - May 5 2016

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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Zhang, H., Kozono, D. E., O'Connor, K. W., Vidal-Cardenas, S., Rousseau, A., Hamilton, A., Moreau, L., Gaudiano, E. F., Greenberger, J., Bagby, G., Soulier, J., Grompe, M., Parmar, K., & D'Andrea, A. D. (2016). TGF-β inhibition rescues hematopoietic stem cell defects and bone marrow failure in Fanconi anemia. Cell Stem Cell, 18(5), 668-681. https://doi.org/10.1016/j.stem.2016.03.002

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 2016, 'TGF-β inhibition rescues hematopoietic stem cell defects and bone marrow failure in Fanconi anemia', Cell Stem Cell, vol. 18, no. 5, pp. 668-681. https://doi.org/10.1016/j.stem.2016.03.002

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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.",

author = "Haojian Zhang and Kozono, {David E.} and O'Connor, {Kevin W.} and Sofia Vidal-Cardenas and Alix Rousseau and Abigail Hamilton and Lisa Moreau and Gaudiano, {Emily F.} and Joel Greenberger and Grover Bagby and Jean Soulier and Markus Grompe and Kalindi Parmar and D'Andrea, {Alan D.}",

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AU - Vidal-Cardenas, Sofia

AU - Rousseau, Alix

AU - Hamilton, Abigail

AU - Moreau, Lisa

AU - Gaudiano, Emily F.

AU - Greenberger, Joel

AU - Bagby, Grover

AU - Soulier, Jean

AU - Grompe, Markus

AU - Parmar, Kalindi

AU - D'Andrea, Alan D.

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N2 - 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.

AB - 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.

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TGF-β inhibition rescues hematopoietic stem cell defects and bone marrow failure in Fanconi anemia

Abstract

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