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

By L. Cimmino, Igor Dolgalev, Yubao Wang, A. Yoshimi, G. Martin, Jingjing Wang, V. Ng, B. Xia, Matthew T. Witkowski, Marisa Mitchell-Flack and 14 more. Cell, 2017

639 citations recorded by the source corpus.

SUMMARY 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 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.

Subfields: Hematology, Molecular Biology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/d41f0cc401a6c3b09ad84ac8f8a92975d92d8b24

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In Hematology

1. M. Valko
2. K. Jomová

In Molecular Biology

1. K. Jomová
2. M. Valko
3. Eugenie Nepovimova

Citations in the corpus

• Several lines of antioxidant defense against oxidative stress: antioxidant enzymes, nanomaterials with multiple enzyme-mimicking activities, and low-molecular-weight antioxidants (2024, background): “The first clinical trials involving patients suffering from various types of advanced cancers treated with vitamin C were conducted in the 1970s (Cimmino et al. 2017).”