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Cell. 2017 Sep 7;170(6):1079-1095.e20. doi: 10.1016/j.cell.2017.07.032. Epub 2017 Aug 17.

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

Author information

1
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA. Electronic address: luisa.cimmino@nyumc.org.
2
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA; Applied Bioinformatics Laboratories, NYU School of Medicine, New York, NY 10016, USA.
3
Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA.
4
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY 10065, USA.
5
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
6
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA.
7
Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
8
Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
9
Australian Center for Blood Diseases, Monash University, VIC 3004, Australia.
10
Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA. Electronic address: benjamin.neel@nyumc.org.
11
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA. Electronic address: iannis.aifantis@nyumc.org.

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.

KEYWORDS:

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

PMID:
28823558
PMCID:
PMC5755977
DOI:
10.1016/j.cell.2017.07.032
[Indexed for MEDLINE]
Free PMC Article

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