Inhibition of TGFβ1 and TGFβ3 promotes hematopoiesis in Fanconi anemia

Alfredo Rodríguez, Chunyu Yang, Elissa Furutani, Benilde García de Teresa, Martha Velázquez, Jessica Filiatrault, Larissa A. Sambel, Tin Phan, Patricia Flores-Guzmán, Silvia Sánchez, Angélica Monsiváis Orozco, Héctor Mayani, Ozge V. Bolukbasi, Anniina Färkkilä, Michael Epperly, Joel Greenberger, Akiko Shimamura, Sara Frías, Markus Grompe, Kalindi ParmarAlan D. D'Andrea

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Fanconi anemia (FA) is a chromosome instability syndrome with congenital abnormalities, cancer predisposition and bone marrow failure (BMF). Although hematopoietic stem and progenitor cell (HSPC) transplantation is the recommended therapy, new therapies are needed for FA patients without suitable donors. BMF in FA is caused, at least in part, by a hyperactive growth-suppressive transforming growth factor β (TGFβ) pathway, regulated by the TGFβ1, TGFβ2, and TGFβ3 ligands. Accordingly, the TGFβ pathway is an attractive therapeutic target for FA. While inhibition of TGFβ1 and TGFβ3 promotes blood cell expansion, inhibition of TGFβ2 is known to suppress hematopoiesis. Here, we report the effects of AVID200, a potent TGFβ1- and TGFβ3-specific inhibitor, on FA hematopoiesis. AVID200 promoted the survival of murine FA HSPCs in vitro. AVID200 also promoted in vitro the survival of human HSPCs from patients with FA, with the strongest effect in patients progressing to severe aplastic anemia or myelodysplastic syndrome (MDS). Previous studies have indicated that the toxic upregulation of the nonhomologous end-joining (NHEJ) pathway accounts, at least in part, for the poor growth of FA HSPCs. AVID200 downregulated the expression of NHEJ-related genes and reduced DNA damage in primary FA HSPC in vitro and in in vivo models. Collectively, AVID200 exhibits activity in FA mouse and human preclinical models. AVID200 may therefore provide a therapeutic approach to improving BMF in FA.

Original languageEnglish (US)
Pages (from-to)70-84.e4
JournalExperimental hematology
StatePublished - Jan 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research


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