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 Figueroa, Ross A. Dickins, Omar Abdel-WahabChristopher Y. Park, Aristotelis Tsirigos, Benjamin G. Neel, Iannis Aifantis

Research output: Contribution to journalArticle

138 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. PaperClip [Formula presented]

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

Fingerprint

Ascorbic Acid
Restoration
Leukemia
DNA
Dioxygenases
Hematopoietic Stem Cells
Stem cells
Genes
Cells
Myelodysplastic Syndromes
Hematopoiesis
Oxidation
RNA Interference
Acute Myeloid Leukemia
Transgenic Mice
Stem Cells
Maintenance
Phenotype
Cell Line
Mutation

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Cimmino, L., Dolgalev, I., Wang, Y., Yoshimi, A., Martin, G. H., Wang, J., ... 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

Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. / Cimmino, Luisa; Dolgalev, Igor; Wang, Yubao; Yoshimi, Akihide; Martin, Gaëlle H.; Wang, Jingjing; Ng, Victor; Xia, Bo; Witkowski, Matthew T.; Mitchell-Flack, Marisa; Grillo, Isabella; Bakogianni, Sofia; Ndiaye-Lobry, Delphine; Martín, Miguel Torres; Guillamot, Maria; Banh, Robert S.; Xu, Mingjiang; Figueroa, Maria; Dickins, Ross A.; Abdel-Wahab, Omar; Park, Christopher Y.; Tsirigos, Aristotelis; Neel, Benjamin G.; Aifantis, Iannis.

In: Cell, Vol. 170, No. 6, 07.09.2017, p. 1079-1095.e20.

Research output: Contribution to journalArticle

Cimmino, L, Dolgalev, I, Wang, Y, Yoshimi, A, Martin, GH, Wang, J, Ng, V, Xia, B, Witkowski, MT, Mitchell-Flack, M, Grillo, I, Bakogianni, S, Ndiaye-Lobry, D, Martín, MT, Guillamot, M, Banh, RS, Xu, M, Figueroa, M, Dickins, RA, Abdel-Wahab, O, Park, CY, Tsirigos, A, Neel, BG & Aifantis, I 2017, 'Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression', Cell, vol. 170, no. 6, pp. 1079-1095.e20. https://doi.org/10.1016/j.cell.2017.07.032
Cimmino L, Dolgalev I, Wang Y, Yoshimi A, Martin GH, Wang J et al. Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell. 2017 Sep 7;170(6):1079-1095.e20. https://doi.org/10.1016/j.cell.2017.07.032
Cimmino, Luisa ; Dolgalev, Igor ; Wang, Yubao ; Yoshimi, Akihide ; Martin, Gaëlle H. ; Wang, Jingjing ; Ng, Victor ; Xia, Bo ; Witkowski, Matthew T. ; Mitchell-Flack, Marisa ; Grillo, Isabella ; Bakogianni, Sofia ; Ndiaye-Lobry, Delphine ; Martín, Miguel Torres ; Guillamot, Maria ; Banh, Robert S. ; Xu, Mingjiang ; Figueroa, Maria ; Dickins, Ross A. ; Abdel-Wahab, Omar ; Park, Christopher Y. ; Tsirigos, Aristotelis ; Neel, Benjamin G. ; Aifantis, Iannis. / Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. In: Cell. 2017 ; Vol. 170, No. 6. pp. 1079-1095.e20.
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AU - Wang, Yubao

AU - Yoshimi, Akihide

AU - Martin, Gaëlle H.

AU - Wang, Jingjing

AU - Ng, Victor

AU - Xia, Bo

AU - Witkowski, Matthew T.

AU - Mitchell-Flack, Marisa

AU - Grillo, Isabella

AU - Bakogianni, Sofia

AU - Ndiaye-Lobry, Delphine

AU - Martín, Miguel Torres

AU - Guillamot, Maria

AU - Banh, Robert S.

AU - Xu, Mingjiang

AU - Figueroa, Maria

AU - Dickins, Ross A.

AU - Abdel-Wahab, Omar

AU - Park, Christopher Y.

AU - Tsirigos, Aristotelis

AU - Neel, Benjamin G.

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N2 - 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]

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