Inhibition of TGF beta 1 and TGF beta 3 promotes hematopoiesis in Fanconi anemia

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 beta (TGF beta) pathway, regulated by the TGF beta 1, TGF beta 2, and TGF beta 3 ligands. Accordingly, the TGF beta pathway is an attractive therapeutic target for FA. While inhibition of TGF beta 1 and TGF beta 3 promotes blood cell expansion, inhibition of TGF beta 2 is known to suppress hematopoiesis. Here, we report the effects of AVID200, a potent TGF beta 1- and TGF beta 3-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. (c) 2020 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.Peer reviewe