Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression.
Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression.
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DOI：
10.1016/j.cell.2017.07.032
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发表时间：
2017-09-07
期刊：
影响因子：
64.5
通讯作者：
Aifantis I
中科院分区：
文献类型：
--
作者：
Cimmino L;Dolgalev I;Wang Y;Yoshimi A;Martin GH;Wang J;Ng V;Xia B;Witkowski MT;Mitchell-Flack M;Grillo I;Bakogianni S;Ndiaye-Lobry D;Martín MT;Guillamot M;Banh RS;Xu M;Figueroa ME;Dickins RA;Abdel-Wahab O;Park CY;Tsirigos A;Neel BG;Aifantis I
TET 2功能缺失突变常发生在克隆性造血、骨髓增生异常综合征（MDS）和急性髓性白血病（AML）患者中，并与DNA高甲基化表型相关。为了确定TET 2缺陷在白血病干细胞维持中的作用，我们产生了可逆的转基因RNAi小鼠以模拟内源性Tet 2表达的恢复。Tet 2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。维生素C（Fe 2+和α-KG依赖性双加氧酶的辅因子）治疗通过增强Tet 2缺陷小鼠HSPC中5-羟甲基胞嘧啶的形成来模拟TET 2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还驱动DNA低甲基化和TET 2依赖性基因签名在人类白血病细胞系中的表达。此外，维生素C治疗诱导的TET介导的DNA氧化增强了白血病细胞对PARP抑制的敏感性，并可提供一种安全有效的组合策略，以选择性靶向癌症中的泰特缺陷。维生素C治疗模拟TET 2恢复对白血病干细胞的作用，并增强PARP抑制在抑制白血病进展中的功效。
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 cofactor 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. Vitamin C treatment mimics the effect of TET2 restoration on leukemic stem cells and enhances the efficacy of PARP inhibition in suppressing leukemia progression.
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DOI：
10.1073/pnas.1612262113
发表时间：
2016-09-13
影响因子：
11.1
作者：
Liu, Minmin;Ohtani, Hitoshi;Jones, Peter A.
通讯作者：
Jones, Peter A.
影响因子：
3.7
作者：
Ciccarone F;Klinger FG;Catizone A;Calabrese R;Zampieri M;Bacalini MG;De Felici M;Caiafa P
通讯作者：
Caiafa P
影响因子：
18.4
作者：
Guillamot M;Cimmino L;Aifantis I
通讯作者：
Aifantis I
影响因子：
12.3
作者：
Akalin A;Kormaksson M;Li S;Garrett-Bakelman FE;Figueroa ME;Melnick A;Mason CE
通讯作者：
Mason CE
影响因子：
2.9
作者：
Fritz, Heidi;Flower, Gillian;Seely, Dugald
通讯作者：
Seely, Dugald