3 years ago

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

Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression
Maria E. Figueroa, Akihide Yoshimi, Christopher Y. Park, Matthew T. Witkowski, Maria Guillamot, Bo Xia, Marisa Mitchell-Flack, Miguel Torres Martín, Victor Ng, Benjamin G. Neel, Mingjiang Xu, Robert S. Banh, Jingjing Wang, Iannis Aifantis, Gaëlle H. Martin, Aristotelis Tsirigos, Omar Abdel-Wahab, Delphine Ndiaye-Lobry, Luisa Cimmino, Isabella Grillo, Ross A. Dickins, Yubao Wang, Igor Dolgalev, Sofia Bakogianni

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 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.

Publisher URL: http://www.cell.com/cell/fulltext/S0092-8674(17)30868-1

DOI: 10.1016/j.cell.2017.07.032

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