@article{5b059530092848bba284b075bf3e36f3,
title = "Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression",
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.",
keywords = "DNA demethylation, DNA oxidation, HSCs, PARP inhibitor, TET2, hydroxymethylcytosine, leukemia, reversible RNAi, self-renewal, vitamin C",
author = "Luisa Cimmino and Igor Dolgalev and Yubao Wang and Akihide Yoshimi and Martin, {Ga{\"e}lle H.} and Jingjing Wang and Victor Ng and Bo Xia and Witkowski, {Matthew T.} and Marisa Mitchell-Flack and Isabella Grillo and Sofia Bakogianni and Delphine Ndiaye-Lobry and Mart{\'i}n, {Miguel Torres} and Maria Guillamot and Banh, {Robert S.} and Mingjiang Xu and Figueroa, {Maria E.} and Dickins, {Ross A.} and Omar Abdel-Wahab and Park, {Christopher Y.} and Aristotelis Tsirigos and Neel, {Benjamin G.} and Iannis Aifantis",
note = "Funding Information: We thank Dr. Mark. D. Minden from the Princess Margaret Cancer Center (Toronto, Canada) for providing primary AML patient samples. We would like to thank Mirimus Inc for expertise in generation and analysis of the ShTet2 animals. We also thank the NYU School of Medicine core facilities including High Performance Computing, Flow Cytometry the Genome Technology Center, Experimental Pathology and Microscopy. The New York University Langone Medical Center Experimental Pathology Research Laboratory (New York, NY, USA) and Microscopy Laboratory (New York, NY, USA) are supported by Cancer Center Support Grant P30 CA016887. This research was supported by the US NIH (RO1 CA216421, R01 CA194923, R01 CA169784, R01 CA133379, R01CA149655, 5R01CA173636, and R01 CA49132), the Leukemia & Lymphoma Society (TRP#6340-11 and LLS#6373-13), Feinberg Lymphoma Pilot Grant (to L.C.), The Chemotherapy Foundation, The V Foundation for Cancer Research, Alex's Lemonade Stand Foundation for Childhood Cancer, St. Baldrick's Cancer Research Foundation (to L.C. and I.A.), and the Howard Hughes Medical Institute (to I.A.). The work was also supported by the New York State Department of Health (CO030132). Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = sep,
day = "7",
doi = "10.1016/j.cell.2017.07.032",
language = "English (US)",
volume = "170",
pages = "1079--1095.e20",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",
}