突变型异柠檬酸脱氢酶1（IDH1）下调共济失调毛细血管扩张突变基因（ATM），并改变DNA修复及对DNA损伤的敏感性，且与四氢叶酸还原酶2（TET2）无关。
Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2.
作者信息
Inoue Satoshi, Li Wanda Y, Tseng Alan, Beerman Isabel, Elia Andrew J, Bendall Sean C, Lemonnier François, Kron Ken J, Cescon David W, Hao Zhenyue, Lind Evan F, Takayama Naoya, Planello Aline C, Shen Shu Yi, Shih Alan H, Larsen Dana M, Li Qinxi, Snow Bryan E, Wakeham Andrew, Haight Jillian, Gorrini Chiara, Bassi Christian, Thu Kelsie L, Murakami Kiichi, Elford Alisha R, Ueda Takeshi, Straley Kimberly, Yen Katharine E, Melino Gerry, Cimmino Luisa, Aifantis Iannis, Levine Ross L, De Carvalho Daniel D, Lupien Mathieu, Rossi Derrick J, Nolan Garry P, Cairns Rob A, Mak Tak W
机构信息
The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON M5G 2C1, Canada; The Princess Margaret Cancer Centre and Ontario Cancer Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON M5G 2C1, Canada; The Princess Margaret Cancer Centre and Ontario Cancer Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
出版信息
Cancer Cell. 2016 Aug 8;30(2):337-348. doi: 10.1016/j.ccell.2016.05.018. Epub 2016 Jul 14.
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 (HSCs), 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.
异柠檬酸脱氢酶-1基因（IDH1）突变是急性髓系白血病（AML）常见的驱动因素，但其机制尚未完全明确。人们认为IDH1突变体通过抑制TET2来改变DNA甲基化发挥作用，但IDH1突变疾病和TET2突变疾病之间存在显著的、无法解释的临床差异。我们发现，与Tet2基因敲除（TET2-KO）小鼠相比，表达内源性突变IDH1的小鼠造血干细胞（HSC）数量减少。突变型IDH1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的敏感性增加以及HSC自我更新减少，这一过程独立于TET2。在人类IDH1突变的AML中，ATM表达也会降低。这些发现可能对IDH突变白血病的治疗具有启示意义。
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