Mutant IDH1 Promotes Glioma Formation In Vivo.
Mutant IDH1 Promotes Glioma Formation In Vivo.
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DOI：
10.1016/j.celrep.2018.03.133
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发表时间：
2018-05-01
期刊：
影响因子：
8.8
通讯作者：
Holmen SL
中科院分区：
文献类型：
--
作者：
Philip B;Yu DX;Silvis MR;Shin CH;Robinson JP;Robinson GL;Welker AE;Angel SN;Tripp SR;Sonnen JA;VanBrocklin MW;Gibbons RJ;Looper RE;Colman H;Holmen SL
异柠檬酸脱氢酶1（IDH 1）是II-III级胶质瘤和继发性胶质母细胞瘤（GBM）中最常见的突变基因。IDH 1 R132 H在神经胶质瘤发生中的因果作用已被提出，但体内功能验证尚未得到证实。在这项研究中，我们评估了IDH 1 R132 H在神经胶质瘤发展中的作用，在临床相关的协作遗传改变的背景下，在体外和体内。表达IDH 1 R132 H的永生星形胶质细胞表现出（R）-2-羟基戊二酸水平升高，NADPH减少，增殖增加和锚定非依赖性生长。尽管IDH 1 R132 H本身并不足够，但它与PDGFA以及Cdkn 2a、Atrx和Pten的缺失协同作用以促进体内胶质瘤的发展。这些肿瘤在遗传学、组织学和功能上类似于促神经人类突变体IDH 1 GBM。我们的研究结果支持IDH 1 R132 H促进胶质瘤发展的假设。该模型增强了我们对IDH 1 R132 H驱动的神经胶质瘤生物学的理解，并促进了旨在对抗这种致命疾病的治疗策略的测试。Philip等人表明突变体IDH 1与PDGFA以及Cdkn 2a、Atrx和Pten的缺失协同作用，以促进胶质瘤小鼠模型中的体内胶质瘤发生。这些肿瘤类似于前神经人突变IDH 1胶质母细胞瘤，并表现出对PARP抑制与化疗联合的敏感性增强。
Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated gene in grade II–III glioma and secondary glioblastoma (GBM). A causal role for IDH1R132H in gliomagenesis has been proposed, but functional validation in vivo has not been demonstrated. In this study, we assessed the role of IDH1R132H in glioma development in the context of clinically relevant cooperating genetic alterations in vitro and in vivo. Immortal astrocytes expressing IDH1R132H exhibited elevated (R)-2-hydroxyglutarate levels, reduced NADPH, increased proliferation, and anchorage-independent growth. Although not sufficient on its own, IDH1R132H cooperated with PDGFA and loss of Cdkn2a, Atrx, and Pten to promote glioma development in vivo. These tumors resembled pro-neural human mutant IDH1 GBM genetically, histologically, and functionally. Our findings support the hypothesis that IDH1R132H promotes glioma development. This model enhances our understanding of the biology of IDH1R132H-driven gliomas and facilitates testing of therapeutic strategies designed to combat this deadly disease. Philip et al. show that mutant IDH1 cooperates with PDGFA and loss of Cdkn2a, Atrx, and Pten to promote gliomagenesis in vivo in a mouse model of glioma. These tumors resemble proneural human mutant IDH1 glioblastoma and exhibit enhanced sensitivity to PARP inhibition in combination with chemotherapy.
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影响因子：
10.5
作者：
Amankulor NM;Kim Y;Arora S;Kargl J;Szulzewsky F;Hanke M;Margineantu DH;Rao A;Bolouri H;Delrow J;Hockenbery D;Houghton AM;Holland EC
通讯作者：
Holland EC
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影响因子：
4.6
作者：
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通讯作者：
Huang J
影响因子：
64.8
作者：
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影响因子：
45.3
作者：
Sanson, Marc;Marie, Yannick;Delattre, Jean-Yves
通讯作者：
Delattre, Jean-Yves
影响因子：
8
作者：
Robinson, J. P.;VanBrocklin, M. W.;Guilbeault, A. R.;Signorelli, D. L.;Brandner, S.;Holmen, S. L.
通讯作者：
Holmen, S. L.