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

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48 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 languageEnglish (US)
Pages (from-to)668-681
Number of pages14
JournalCell Stem Cell
Volume18
Issue number5
DOIs
Publication statusPublished - May 5 2016

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ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

Cite this

Zhang, H., Kozono, D. E., O'Connor, K. W., Vidal-Cardenas, S., Rousseau, A., Hamilton, A., ... 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