TGF-B Inhibition Rescues Hematopoietic Defects in Fanconi Anemia

Four different combinations of double knock-out mouse strains have been created (SMAD3-/- Fancd2-/-) consisting of combinations of the individual knock-out strains on either the C57BL/6 or 129/Sv background. Sets of breeding experiments were carried out and the frequency of detection of double knock-out mice was significantly below the expected frequency of detecting DKO mice by breeding double heterozygotes (1 out of 16 or 6.25%). In fact, DKO mice were detected at a frequency ranging from 3.4% to 0.54%. Mice of all four DKO genotypes showed resistance of bone marrow hematopoietic progenitor cells to canonical TGF-β signaling, consistent with the SMAD3-/- parent. However, the predominant phenotype was that of the Fancd2-/- parent including reduced duration of hematopoiesis in long-term bone marrow cultures, reduced marrow stem cell competitive repopulation capacity, and retained mitomycin C and radiation sensitivity of bone marrow stromal cells. These mice should be a valuable resource for elucidating the bypass pathways involved in the reduced, but successful gestation of SMAD3-/- Fancd2-/- mice, and the interactions of the FA and TGF-β signaling pathways.Supported by the NIAID/NIH U19-A168021 and the Fanconi Anemia Research Fund.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - Category: Hematology Authors: Tags: New Approaches to Correcting the Defect in Inherited Bone Marrow Failure Syndromes Source Type: research