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Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression.
Cell ( IF 45.5 ) Pub Date : 2017-Sep-07 , DOI: 10.1016/j.cell.2017.07.032
Luisa Cimmino 1 , Igor Dolgalev 2 , Yubao Wang 3 , Akihide Yoshimi 4 , Gaëlle H Martin 5 , Jingjing Wang 1 , Victor Ng 5 , Bo Xia 5 , Matthew T Witkowski 1 , Marisa Mitchell-Flack 1 , Isabella Grillo 1 , Sofia Bakogianni 1 , Delphine Ndiaye-Lobry 1 , Miguel Torres Martín 6 , Maria Guillamot 1 , Robert S Banh 3 , Mingjiang Xu 7 , Maria E Figueroa 6 , Ross A Dickins 8 , Omar Abdel-Wahab 4 , Christopher Y Park 5 , Aristotelis Tsirigos 2 , Benjamin G Neel 3 , Iannis Aifantis 1
Affiliation  

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.

中文翻译:

TET2 功能的恢复可阻止异常的自我更新和白血病进展。

TET2 功能丧失突变经常发生在克隆性造血、骨髓增生异常综合征 (MDS) 和急性髓系白血病 (AML) 患者中,并且与 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,我们生成了一个可逆的转基因 RNAi 小鼠来模拟内源性 Tet2 表达的恢复。Tet2 恢复在体外和体内逆转异常的造血干细胞和祖细胞 (HSPC) 自我更新。用维生素 C(Fe2 +的辅助因子)处理和 α-KG 依赖性双加氧酶,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 恢复,并抑制人类白血病集落形成和原发性人类白血病 PDX 的白血病进展。维生素 C 还驱动 DNA 低甲基化和人类白血病细胞系中 TET2 依赖性基因特征的表达。此外,白血病细胞中由维生素 C 治疗诱导的 TET 介导的 DNA 氧化增强了它们对 PARP 抑制的敏感性,并且可以提供一种安全有效的联合策略,以选择性地靶向癌症中的 TET 缺乏症。回形针。
更新日期:2017-08-17
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