Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell stem cell, 2018-09, Vol.23 (3), p.355-369.e9

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •SIRT1 depletion enhances MDS HSPC self-renewal and growth•SIRT1 insufficiency in MDS promotes TET2 hyperacetylation•SIRT1 agonist treatment blocks MDS HSPC maintenance•SIRT1 activation deacetylates TET2 and enhances its catalytic activity 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.