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 journalArticle

197 Scopus citations

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. PaperClip [Formula presented]

Original languageEnglish (US)
Pages (from-to)1079-1095.e20
JournalCell
Volume170
Issue number6
DOIs
StatePublished - Sep 7 2017

Keywords

  • DNA demethylation
  • DNA oxidation
  • HSCs
  • PARP inhibitor
  • TET2
  • hydroxymethylcytosine
  • leukemia
  • reversible RNAi
  • self-renewal
  • vitamin C

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Cimmino, L., Dolgalev, I., Wang, Y., Yoshimi, A., Martin, G. H., Wang, J., Ng, V., Xia, B., Witkowski, M. T., Mitchell-Flack, M., Grillo, I., Bakogianni, S., Ndiaye-Lobry, D., Martín, M. T., Guillamot, M., Banh, R. S., Xu, M., Figueroa, M. E., Dickins, R. A., ... Aifantis, I. (2017). Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell, 170(6), 1079-1095.e20. https://doi.org/10.1016/j.cell.2017.07.032