Fanconi anemia is a genetic
bone marrow failure syndrome. The current treatment options are suboptimal and do not prevent the eventual onset of
aplastic anemia requiring
bone marrow transplantation. We previously showed that
resveratrol, an
antioxidant and an activator of the
protein deacetylase
Sirt1, enhanced hematopoiesis in Fancd2 mutant mice and improved the impaired stem cell quiescence observed in this disease. Given that
Sirt1 is important for the function of hematopoietic stem cells, we hypothesized that
Sirt1 activation may improve hematopoiesis. Indeed, Fancd2(-/-) mice and wild-type mice treated with the selective
Sirt1 activator
SRT3025 had increased numbers of hematopoietic stem and progenitor cells, platelets and white blood cells.
SRT3025 was also protective against
acetaldehyde-induced hematopoietic damage. Unlike
resveratrol, however,
SRT3025 did not affect stem cell quiescence, suggesting distinct mechanisms of action. Conditional deletion of
Sirt1 in hematopoietic cells did not abrogate the beneficial effects of
SRT3025, indicating that the
drug did not act by directly stimulating
Sirt1 in stem cells, but must be acting indirectly via extra-hematopoietic effects.
RNA-Seq transcriptome analysis revealed the down-regulation of Egr1-p21 expression, providing a potential mechanism for improved hematopoiesis. Overall, our data indicate that
SRT3025 or related compounds may be beneficial in
Fanconi anemia and other
bone marrow failure syndromes.