Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2.
Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2.
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DOI：
10.1016/j.ccell.2016.05.018
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发表时间：
2016-08-08
期刊：
影响因子：
50.3
通讯作者：
Mak TW
中科院分区：
文献类型：
--
作者：
Inoue S;Li WY;Tseng A;Beerman I;Elia AJ;Bendall SC;Lemonnier F;Kron KJ;Cescon DW;Hao Z;Lind EF;Takayama N;Planello AC;Shen SY;Shih AH;Larsen DM;Li Q;Snow BE;Wakeham A;Haight J;Gorrini C;Bassi C;Thu KL;Murakami K;Elford AR;Ueda T;Straley K;Yen KE;Melino G;Cimmino L;Aifantis I;Levine RL;De Carvalho DD;Lupien M;Rossi DJ;Nolan GP;Cairns RA;Mak TW
异柠檬酸脱氢酶-1基因（IDH 1）的突变是急性髓细胞白血病（AML）的常见驱动因素，但其机制尚未完全了解。IDH 1突变体被认为通过抑制TET 2来改变DNA甲基化，但IDH 1和TET 2突变疾病之间存在显著的无法解释的临床差异。我们已经发现，与Tet 2敲除（TET 2-KO）小鼠相比，表达内源性突变体IDH 1的小鼠具有减少的造血干细胞（HSC）数量。突变IDH 1通过改变组蛋白甲基化下调DNA损伤（DD）传感器ATM，导致DNA修复受损，对DD的敏感性增加，并减少HSC自我更新，独立于TET 2。ATM表达在人IDH 1突变的AML中也降低。这些发现可能对IDH突变型白血病的治疗有意义。
Mutations in the isocitrate dehydrogenase-1 gene (IDH1) are common drivers of acute myeloid leukemia (AML) but their mechanism is not fully understood. It is thought that IDH1 mutants act by inhibiting TET2 to alter DNA methylation, but there are significant unexplained clinical differences between IDH1- and TET2-mutant diseases. We have discovered that mice expressing endogenous mutant IDH1 have reduced numbers of hematopoietic stem cells (HSC), in contrast to Tet2 knockout (TET2-KO) mice. Mutant IDH1 downregulates the DNA damage (DD) sensor ATM by altering histone methylation, leading to impaired DNA repair, increased sensitivity to DD, and reduced HSC self-renewal, independent of TET2. ATM expression is also decreased in human IDH1-mutated AML. These findings may have implications for treatment of IDH-mutant leukemia.
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影响因子：
30.8
作者：
Busque L;Patel JP;Figueroa ME;Vasanthakumar A;Provost S;Hamilou Z;Mollica L;Li J;Viale A;Heguy A;Hassimi M;Socci N;Bhatt PK;Gonen M;Mason CE;Melnick A;Godley LA;Brennan CW;Abdel-Wahab O;Levine RL
通讯作者：
Levine RL
影响因子：
10.5
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Chen C;Liu Y;Lu C;Cross JR;Morris JP 4th;Shroff AS;Ward PS;Bradner JE;Thompson C;Lowe SW
通讯作者：
Lowe SW
影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
30.5
作者：
Cimmino L;Dawlaty MM;Ndiaye-Lobry D;Yap YS;Bakogianni S;Yu Y;Bhattacharyya S;Shaknovich R;Geng H;Lobry C;Mullenders J;King B;Trimarchi T;Aranda-Orgilles B;Liu C;Shen S;Verma AK;Jaenisch R;Aifantis I
通讯作者：
Aifantis I