Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression
Publication information:
Cimmino, L.; Dolgalev, I.; Wang, Y.; Yoshimi, A.; Martin, G.; Wang, J.; Ng, V.; Xia, B.; Witkowski, M.; Mitchell-Flack, M.; Grillo, I.; Bakogianni, S.; Ndiaye-Lobry, D.; Martín, M. T.; Guillamot, M.; Banh, R.; Xu, M.; Figueroa, M.; Dickins, R.; Abdel-Wahab, O.; Park, C.; Tsirigos, A.; Neel, B.; Aifantis, I.
Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell 2017, 170 (6), 1079-1095.e20. https://doi.org/10.1016/j.cell.2017.07.032.
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. PAPERCLIP.