Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression

Luisa Cimmino, Igor Dolgalev, Yubao Wang, Akihide Yoshimi, Gaëlle H. Martin, Jingjing Wang, Victor Ng, Bo Xia, Matthew T Witkowski, Marisa Mitchell-Flack, Isabella Grillo, Sofia Bakogianni, Delphine Ndiaye-Lobry, Miguel Torres Martín, Maria Guillamot, Robert S. Banh, Mingjiang Xu, Maria E Figueroa, Ross A. Dickins, Omar Abdel-WahabChristopher Y. Park, Aristotelis Tsirigos, Benjamin G Neel, Iannis Aifantis

Research output: Contribution to journalArticleResearchpeer-review

230 Citations (Scopus)

Abstract

Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a co-factor of Fe2+ and α-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs. Vitamin C also drives DNA hypomethylation and expression of a TET2-dependent gene signature in human leukemia cell lines. Furthermore, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer. Vitamin C treatment mimics the effect of TET2 restoration on leukemic stem cells and enhances the efficacy of PARP inhibition in suppressing leukemia progression.

Original languageEnglish
Pages (from-to)1079 - 1095.e20
Number of pages17
JournalCell
Volume170
Issue number6
DOIs
Publication statusPublished - 7 Sep 2017

Keywords

  • DNA demethylation
  • DNA oxidation
  • HSCs
  • Hydroxymethylcytosine
  • Leukemia
  • PARP inhibitor
  • Reversible RNAi
  • Self-renewal
  • TET2
  • Vitamin C

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