Induction of TGF-β by Irradiation or Chemotherapy in Fanconi Anemia (FA) Mouse Bone Marrow Is Modulated by Small Molecule Radiation Mitigators JP4-039 and MMS350

Total-body irradiation and/or administration of chemotherapy drugs in bone marrow transplantation induce cytokines that can suppress engraftment. Fanconi Anemia (FA) patients have a hyperactive responsiveness to the inhibitory cytokine, transforming growth factor-beta (TGF-β). Small molecule radiation mitigator drugs, JP4-039 and MMS350, were evaluated for suppression of irradiation or drug-induced TGF-β.In vivo induction of TGF-β by total-body ionizing irradiation (TBI), L-phenylalanine mustard (L-PAM), busulfan or fludarabine, was quantified. In parallel, mitigator drug amelioration of TGF-β induction in FA D2-/- (FANCD2-/-) mouse bone marrow, was studied in vitro. Tissue culture medium, cell lysates, and mouse plasma were analyzed for TGF-β levels.Induction of TGF-β levels in FANCD2-/- and FANCD2+/+ mice and in mouse bone marrow were modulated by both JP4-039 and MMS350.Bone marrow transplantation in FA recipients may benefit from administration of small molecule agents that suppress TGF-β induction.