Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression
Open accessAbstract
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.
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In an inducible TET2-deletion mouse leukaemia model, daily intraperitoneal high-dose ascorbate (4 g kg−1) reproduced TET2 restoration by increasing DNA demethylation and myeloid differentiation genes.
“daily intraperitoneal injection of high-dose ascorbate (4 g kg−1) treatment in an inducible TET2 deletion mouse model of leukaemia recapitulated the TET2 restoration phenotypes by promoting DNA demethylation and the expression of genes critical for myeloid cell differentiation67.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [67]
In genetic mouse models of leukaemia, vitamin C increases DNA demethylation.
“Using genetic mouse models of leukaemia, vitamin C is shown to enhance TET2 activity, increase DNA demethylation and suppress leukaemia progression.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [67]
In genetic mouse models of leukaemia, vitamin C suppresses leukaemia progression.
“Using genetic mouse models of leukaemia, vitamin C is shown to enhance TET2 activity, increase DNA demethylation and suppress leukaemia progression.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [67]
In genetic mouse models of leukaemia, vitamin C enhances TET2 activity.
“Using genetic mouse models of leukaemia, vitamin C is shown to enhance TET2 activity, increase DNA demethylation and suppress leukaemia progression.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [67]
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References 46 · Cited by 707
- Authors
- 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., Abdel-Wahab, O., Park, C. Y., Tsirigos, A., Neel, B. G., & Aifantis, I.
- Affiliations
- NYU Langone Health (US)
- NYU Langone’s Laura and Isaac Perlmutter Cancer Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Miami (US)
- Monash University (AU)
- Corresponding author
- Cimmino, Luisa
- Neel, Benjamin G.
- Aifantis, Iannis
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 170
- Issue
- 6
- Pages
- 1079-1095.e20
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5755977
- OpenAlex
- W2746871805
- Cited by
- 707
- References
- 46
- Citations by year
- 2026: 50 · 2025: 72 · 2024: 60 · 2023: 80 · 2022: 82 · 2021: 93 · 2020: 112 · 2019: 66 · 2018: 76 · 2017: 16
- FWCI
- 56.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Center Support Grant (P30 CA016887)
- US NIH (RO1 CA216421, R01 CA194923, R01 CA169784, R01 CA133379, R01CA149655, 5R01CA173636, R01 CA49132)
- Leukemia & Lymphoma Society (TRP#6340-11, LLS#6373-13)
- Feinberg Lymphoma Pilot Grant
- The Chemotherapy Foundation
- The 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)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- TET2, leukemia stem cells, hematopoietic stem and progenitor cells, self-renewal, acute myeloid leukemia, clonal hematopoiesis, myelodysplastic syndrome, DNA hypermethylation, 5-hydroxymethylcytosine, vitamin C, DNA oxidation, PARP inhibition, DNA demethylation, leukemia progression
- MeSH terms
- Poly (ADP-Ribose) Polymerase-1, Animals, Ascorbic Acid, DNA-Binding Proteins, Humans, Myelodysplastic Syndromes, Neoplasm Transplantation, Proto-Oncogene Proteins, Transcription, Genetic, Transplantation, Heterologous, Vitamins, Leukemia, Myeloid, Acute, Cell Death, DNA Methylation, Cell Line, Tumor, Dioxygenases, Mice, Gene Knockdown Techniques
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