Journal
CELL
Volume 170, Issue 6, Pages 1079-1095Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.07.032
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Funding
- Cancer Center Support Grant [P30 CA016887]
- US NIH [RO1 CA216421, R01 CA194923, R01 CA169784, R01 CA133379, R01CA149655, 5R01CA173636, R01 CA49132]
- Leukemia & Lymphoma Society [6340-11, 6373-13]
- Feinberg Lymphoma Pilot Grant
- Chemotherapy Foundation
- V Foundation for Cancer Research
- Alex's Lemonade Stand Foundation for Childhood Cancer
- St. Baldrick's Cancer Research Foundation
- Howard Hughes Medical Institute
- New York State Department of Health [CO030132]
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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 cofactor of Fe2+ and alpha-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.
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