Cimmino Luisa, Dolgalev Igor, Wang Yubao, Yoshimi Akihide, Martin Gaëlle H, Wang Jingjing, Ng Victor, Xia Bo, Witkowski Matthew T, Mitchell-Flack Marisa, Grillo Isabella, Bakogianni Sofia, Ndiaye-Lobry Delphine, Martín Miguel Torres, Guillamot Maria, Banh Robert S, Xu Mingjiang, Figueroa Maria E, Dickins Ross A, Abdel-Wahab Omar, Park Christopher Y, Tsirigos Aristotelis, Neel Benjamin G, Aifantis Iannis
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA.
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA; Applied Bioinformatics Laboratories, NYU School of Medicine, New York, NY 10016, USA.
Cell. 2017 Sep 7;170(6):1079-1095.e20. doi: 10.1016/j.cell.2017.07.032. Epub 2017 Aug 17.
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.
TET2功能缺失突变在克隆性造血、骨髓增生异常综合征（MDS）和急性髓系白血病（AML）患者中频繁出现，并与DNA高甲基化表型相关。为了确定TET2缺陷在白血病干细胞维持中的作用，我们构建了一种可逆的转基因RNAi小鼠，以模拟内源性Tet2表达的恢复。Tet2的恢复在体外和体内逆转了造血干祖细胞（HSPC）异常的自我更新。维生素C是Fe2和α-KG依赖性双加氧酶的辅助因子，通过增强Tet2缺陷小鼠HSPC中5-羟甲基胞嘧啶的形成来模拟TET2的恢复，并抑制人白血病集落形成和原发性人白血病PDX的白血病进展。维生素C还能驱动人白血病细胞系中的DNA去甲基化和TET2依赖性基因特征的表达。此外，维生素C处理在白血病细胞中诱导的TET介导的DNA氧化增强了它们对PARP抑制的敏感性，并可能提供一种安全有效的联合策略来选择性靶向癌症中的TET缺陷。回形针。
