Convergence of BMI1 and CHD7 on ERK Signaling in Medulloblastoma.
Convergence of BMI1 and CHD7 on ERK Signaling in Medulloblastoma.
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DOI：
10.1016/j.celrep.2017.11.021
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发表时间：
2017-12-05
期刊：
影响因子：
8.8
通讯作者：
Marino S
中科院分区：
文献类型：
--
作者：
Badodi S;Dubuc A;Zhang X;Rosser G;Da Cunha Jaeger M;Kameda-Smith MM;Morrissy AS;Guilhamon P;Suetterlin P;Li XN;Guglielmi L;Merve A;Farooq H;Lupien M;Singh SK;Basson MA;Taylor MD;Marino S
我们描述了BMI 1和CHD 7在髓母细胞瘤发生中的分子趋同。在小鼠模型的功能性基因组筛选中发现，髓母细胞瘤中的BMI 1高; CHD 7低表达特征表征了总生存率低的患者。我们表明，BMI 1介导的ERK 1/2通路的抑制导致原代人MB细胞和异种移植模型中的增殖和肿瘤负荷分别增加。我们提供的证据表明，抑制ERK抑制剂DUSP 4的BMI 1是依赖于一个更容易的染色质配置在G4 MB细胞与低CHD 7表达。这些发现扩展了目前对BMI 1和CHD 7在髓母细胞瘤发病机制中的作用的认识，并且它们提高了BMI 1或ERK的药理学靶向可能特别适用于CHD 7表达水平低的MB亚组的可能性。CHD 7失活在Bmi 1过表达小鼠的正向遗传筛选中诱导MB A BMI 1High; CHD 7 Low签名在总体存活率差的MB患者中发现CHD 7 Low有利于PcG靶基因处的染色质可及性ERK过度活性增加BMI 1High中的增殖和肿瘤负荷; CHD 7 Low MB Badodi et al.发现染色质修饰剂BMI 1和CHD 7在髓母细胞瘤发病机制中的趋同，并且他们表明该途径通过ERK信号传导调节肿瘤增殖和生长。
We describe molecular convergence between BMI1 and CHD7 in the initiation of medulloblastoma. Identified in a functional genomic screen in mouse models, a BMI1High;CHD7Low expression signature within medulloblastoma characterizes patients with poor overall survival. We show that BMI1-mediated repression of the ERK1/2 pathway leads to increased proliferation and tumor burden in primary human MB cells and in a xenograft model, respectively. We provide evidence that repression of the ERK inhibitor DUSP4 by BMI1 is dependent on a more accessible chromatin configuration in G4 MB cells with low CHD7 expression. These findings extend current knowledge of the role of BMI1 and CHD7 in medulloblastoma pathogenesis, and they raise the possibility that pharmacological targeting of BMI1 or ERK may be particularly indicated in a subgroup of MB with low expression levels of CHD7. CHD7 inactivation induces MB in a forward genetic screen in Bmi1-overexpressing mice A BMI1High;CHD7Low signature is found in MB patients with poor overall survival CHD7Low favors chromatin accessibility at PcG target genes ERK overactivity increases proliferation and tumor burden in BMI1High;CHD7Low MB Badodi et al. find convergence of the chromatin modifiers BMI1 and CHD7 in medulloblastoma pathogenesis, and they show that this pathway regulates tumor proliferation and growth via ERK signaling.
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影响因子：
50.3
作者：
Gargiulo, Gaetano;Cesaroni, Matteo;van Lohuizen, Maarten
通讯作者：
van Lohuizen, Maarten
DOI：
10.1073/pnas.1318639110
发表时间：
2013-11-12
影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
64.8
作者：
Lin, Charles Y.;Erkek, Serap;Tong, Yiai;Yin, Linlin;Federation, Alexander J.;Zapatka, Marc;Haldipur, Parthiv;Kawauchi, Daisuke;Risch, Thomas;Warnatz, Hans-Joerg;Worst, Barbara C.;Ju, Bensheng;Orr, Brent A.;Zeid, Rhamy;Polaski, Donald R.;Segura-Wang, Maia;Waszak, Sebastian M.;Jones, David T. W.;Kool, Marcel;Hovestadt, Volker;Buchhalter, Ivo;Sieber, Laura;Johann, Pascal;Chavez, Lukas;Groeschel, Stefan;Ryzhova, Marina;Korshunov, Andrey;Chen, Wenbiao;Chizhikov, Victor V.;Millen, Kathleen J.;Amstislavskiy, Vyacheslav;Lehrach, Hans;Yaspo, Marie-Laure;Eils, Roland;Lichter, Peter;Korbel, Jan O.;Pfister, Stefan M.;Bradner, James E.;Northcott, Paul A.
通讯作者：
Northcott, Paul A.