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 journalArticle

44 Citations (Scopus)

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
StatePublished - May 5 2016

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Fanconi Anemia
Transforming Growth Factors
Hematopoietic Stem Cells
Bone Marrow
Recombinational DNA Repair
Growth
DNA Repair
Small Interfering RNA
Therapeutics
Fibroblasts
Genome

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

TGF-β inhibition rescues hematopoietic stem cell defects and bone marrow failure in Fanconi anemia. / Zhang, Haojian; Kozono, David E.; O'Connor, Kevin W.; Vidal-Cardenas, Sofia; Rousseau, Alix; Hamilton, Abigail; Moreau, Lisa; Gaudiano, Emily F.; Greenberger, Joel; Bagby, Grover; Soulier, Jean; Grompe, Markus; Parmar, Kalindi; D'Andrea, Alan D.

In: Cell Stem Cell, Vol. 18, No. 5, 05.05.2016, p. 668-681.

Research output: Contribution to journalArticle

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
Zhang H, Kozono DE, O'Connor KW, Vidal-Cardenas S, Rousseau A, Hamilton A et al. TGF-β inhibition rescues hematopoietic stem cell defects and bone marrow failure in Fanconi anemia. Cell Stem Cell. 2016 May 5;18(5):668-681. https://doi.org/10.1016/j.stem.2016.03.002
Zhang, Haojian ; Kozono, David E. ; O'Connor, Kevin W. ; Vidal-Cardenas, Sofia ; Rousseau, Alix ; Hamilton, Abigail ; Moreau, Lisa ; Gaudiano, Emily F. ; Greenberger, Joel ; Bagby, Grover ; Soulier, Jean ; Grompe, Markus ; Parmar, Kalindi ; D'Andrea, Alan D. / TGF-β inhibition rescues hematopoietic stem cell defects and bone marrow failure in Fanconi anemia. In: Cell Stem Cell. 2016 ; Vol. 18, No. 5. pp. 668-681.
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