SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function

Abstract

Myelodysplastic syndrome (MDS), a largely incurable hematological malignancy, is derived from aberrant clonal hematopoietic stem/progenitor cells (HSPCs) that persist after conventional therapies. Defining the mechanisms underlying MDS HSPC maintenance is critical for developing MDS therapy. The deacetylase SIRT1 regulates stem cell proliferation, survival, and self-renewal by deacetylating downstream proteins. Here we show that SIRT1 protein levels were downregulated in MDS HSPCs. Genetic or pharmacological activation of SIRT1 inhibited MDS HSPC functions, whereas SIRT1 deficiency enhanced MDS HSPC self-renewal. Mechanistically, the inhibitory effects of SIRT1 were dependent on TET2, a safeguard against HSPC transformation. SIRT1 deacetylated TET2 at conserved lysine residues in its catalytic domain, enhancing TET2 activity. Our genome-wide analysis identified cancer-related genes regulated by the SIRT1/TET2 axis. SIRT1 activation also inhibited functions of MDS HSPCs from patients with TET2 heterozygous mutations. Altogether, our results indicate that restoring TET2 function through SIRT1 activation represents a promising means to target MDS HSPCs.

Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia

“…6c). We observed K1299, K1310, and K1905 were acetylated along with previously reported lysines (K1472/1473/1478) 33 . Nearly complete series of b-ions and y-ions were observed and unambiguously assigned to specific indicated peptide sequences.…”

“…Our results suggest AA effects on TET2 activity may be attenuated by several layers of regulations of TET2, explaining potential variability of AA treatment results in different models. For example, phosphorylation of tyrosine or serine/threonine residues of TET2 enhances its stability and activity 48 and acetylation of N-and C-terminal lysines exert opposite effects on TET2 activity 33,34 . N-terminal lysine acetylation increases TET2 protein level by preventing proteasome mediated degradation 30 .…”

Spliceosomopathies: Diseases and mechanisms

“…In MDS, the splicing of key regulators of hematopoiesis is disrupted, affecting processes such as iron transport, 44 regulation of granulopoiesis, 45 and hematopoietic stem cell maintenance. 46 SF3B1 mutant cell lines were found to have differential expression of genes involved in iron homeostasis and MDS pathogenesis, as well as mitochondrial metabolism and RNA splicing. 47 On the other hand, aberrant splicing of certain kinases in MDS results in hyperactivation of NF-κB signaling pathway, disrupting normal physiological processes in the cells and promoting malignant precursors.…”

Energy metabolism and drug response in myeloid leukaemic stem cells

“…In AML, SIRT1 was shown to be activated by c‐MYC, promoting maintenance and drug resistance in FLT3‐ITD‐positive AML LSCs (Li et al , ). More recently, SIRT1 was shown to also be activated in MDS, resulting in disruption of stem and progenitor cell maintenance by restoring TET2 function (Sun et al , ). Nevertheless, SIRT1 also plays a role in normal haematopoiesis, maintaining HSC homeostasis under conditions of oxidative stress or nutrient deprivation (Singh et al , ), suggesting that SIRT1 inhibition may have pleiotropic effects.…”