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

Jie Sun, Xin He, Yinghui Zhu, Zonghui Ding, Haojie Dong, Yimei Feng, Juan Du, Hanying Wang, Xiwei Wu, Lei Zhang, Xiaochun Yu, Allen Lin, Tinisha McDonald, Dandan Zhao, Herman Wu, Wei Kai Hua, Bin Zhang, Lifeng Feng, Kaoru Tohyama, Ravi BhatiaPhilipp Oberdoerffer, Yang Jo Chung, Peter D. Aplan, Jacqueline Boultwood, Andrea Pellagatti, Samer Khaled, Marcin Kortylewski, Flavia Pichiorri, Ya Huei Kuo, Nadia Carlesso, Guido Marcucci, Hongchuan Jin, Ling Li

Research output: Contribution to journalArticle

14 Scopus citations

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. An improved understanding of the mechanisms regulating myelodysplastic syndrome (MDS) hematopoietic stem/progenitor cell (HSPC) growth and self-renewal is critical for developing MDS therapy. Sun et al. report that SIRT1 deficiency-induced TET2 hyperacetylation promotes MDS HSPC function and provides an approach to target MDS HSPCs by activating SIRT1 deacetylase.

Original languageEnglish (US)
Pages (from-to)355-369.e9
JournalCell Stem Cell
Volume23
Issue number3
DOIs
StatePublished - Sep 6 2018

Keywords

  • HSPCs
  • SIRT1
  • SRT1720
  • TET2
  • acetylation
  • myelodysplastic syndrome

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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    Sun, J., He, X., Zhu, Y., Ding, Z., Dong, H., Feng, Y., Du, J., Wang, H., Wu, X., Zhang, L., Yu, X., Lin, A., McDonald, T., Zhao, D., Wu, H., Hua, W. K., Zhang, B., Feng, L., Tohyama, K., ... Li, L. (2018). SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function. Cell Stem Cell, 23(3), 355-369.e9. https://doi.org/10.1016/j.stem.2018.07.018