SIRT1 depletion enhances the maintenance and self-renewal of myelodysplastic syndrome (MDS) HSPCs.

  • Major finding: SIRT1 depletion enhances the maintenance and self-renewal of myelodysplastic syndrome (MDS) HSPCs.

  • Mechanism: miR-9 and miR-34a deplete SIRT1, resulting in hyperacetylation of TET2, reducing TET2 activity in MDS.

  • Impact: Therapeutic activation of SIRT1 may be a potential therapeutic approach to treat patients with MDS.

Myelodysplastic syndrome (MDS) is a hematopoietic disorder that derives from aberrant clonal hematopoietic stem/progenitor cells (HSPC) that often evade conventional therapies. Loss-of-function mutations in TET2 occur frequently in MDS, and lead to DNA hypermethylation, as TET2 oxidizes methylated cytosine to 5-hydroxymethylcytosine (5hmC) to initiate DNA demethylation. However, a subset of patients with TET wild-type MDS exhibit reduced 5hmC levels, suggesting post-translational regulation of TET2. Sun and colleagues found that the deacetylase SIRT1 acts on TET2 to prevent HSPC maintenance and self-renewal. HSPCs from MDS specimens exhibited reduced expression of SIRT1 along with increased expression of the SIRT1-targeting miRNAs miR-9 and miR-34a, suggesting that SIRT1 is downregulated by miRNAs in MDS. SIRT1 deficiency was associated with enhanced cell growth and self-renewal. SIRT1 activation suppressed MDS cell growth by directly deacetylating TET2, resulting in 5hmC enrichment at target loci and upregulation of target genes. Activation of SIRT1 with the small-molecule agonist SRT1720 reduced TET2 acetylation, enhanced TET2 catalytic activity, and inhibited MDS HSPC colony formation. In vivo, SRT1720 suppressed MDS cell engraftment into mouse bone marrow. Further, in a mouse model of MDS, treatment with SRT1720 reversed the dysplastic phenotypes. Taken together, these findings demonstrate that SIRT1 deficiency induced TET2 hyperacetylation that enhances the maintenance and self-renewal of MDS HSPC. These data suggest the potential for therapeutic activation of SIRT1 as treatment strategy for patients with MDS.

Sun J, He X, Zhu Y, Ding Z, Dong H, Feng Y, et al. SIRT1 activation disrupts maintenance of myelodysplastic syndrome stem and progenitor cells by restoring TET2 function. Cell Stem Cell 2018 Aug 15 [Epub ahead of print].

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©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.