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 journalArticlepeer-review

110 Scopus citations


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
Issue number5
StatePublished - May 5 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology


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