| First Author | Cimmino L | Year | 2017 |
| Journal | Cell | Volume | 170 |
| Issue | 6 | Pages | 1079-1095.e20 |
| PubMed ID | 28823558 | Mgi Jnum | J:252191 |
| Mgi Id | MGI:5927079 | Doi | 10.1016/j.cell.2017.07.032 |
| Citation | Cimmino L, et al. (2017) Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell 170(6):1079-1095.e20 |
| abstractText | 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 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. PAPERCLIP. |
