The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice

Abstract

Fanconi anemia is a genetic bone marrow failure syndrome. 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. RNASeq 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.

Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice

“…38 New therapeutic approaches that have the ability to treat or prevent bone marrow failure and cancer are thus clearly needed for FA. 8,9,20,37,42 Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2 2/2 mutant mice. Of note, metformin is the first compound to improve both of these FA phenotypes: oxymetholone, 9 resveratrol, 8 sirtuin activator, 20 and N-acetylcysteine 42 all improve hematopoiesis in Fancd2 2/2 mice, but none has been shown to diminish tumor incidence.…”

“…37 Our results indicate that metformin can ameliorate both of these key phenotypes of FA, and that its beneficial action was specific to FA mutant mice. In contrast, oxymetholone and the sirtuin activator SRT3025 affect both wild-type and mutant stem cells equally, 9,20 indicating that their mechanisms of action do not target the pathophysiology of FA bone marrow failure. Furthermore, it is particularly intriguing that the chronic administration of metformin significantly increases the frequency of HSCs in the adult Fancd2 2/2 mice.…”

“…9,20 We next focused on characterizing the bone marrow of mice in this cohort. The marrow cellularity in either Fancd2 Figure 1B), was significantly increased by 48% after 6 months of chronic metformin administration ( Figure 1C).…”

“…19 However, we have recently demonstrated that a potent sirtuin activator, SRT3025, does not mimic the effects of resveratrol in FA mice. 20 Given that AMPK plays an important role in HSCs, 21 AMPK activation may be the primary mechanism by which resveratrol improves hematopoiesis. The ability of metformin to activate AMPK and act as a potential aldehyde scavenger makes metformin a potential candidate for the treatment of FA.…”

The progress of early growth response factor 1 and leukemia

“…Loss of the EGR1 gene with deletions of 7q31 or TP53 alone played a role in at least two signaling molecules of genipin-induced apoptosis in gastric cancer cells (88). Another article revealed that the down-regulation of EGR1-p21 expression provides a mechanism for improved hematopoiesis (89). Histone deacetylase (HDAC) inhibitors can reactivate EGR1 in various cell types, leading to decreased cell proliferation and increased cell apoptosis (90).…”