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000130928 0247_ $$2ISSN$$a1365-2141
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000130928 1001_ $$00000-0002-4024-4291$$aWu, Bian$$b0$$eFirst author
000130928 245__ $$aMED12 mutations and NOTCH signalling in chronic lymphocytic leukaemia.
000130928 260__ $$aOxford [u.a.]$$bWiley-Blackwell55962$$c2017
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000130928 520__ $$aMutations in the N-terminus of MED12 protein occur at high frequency in uterine leiomyomas and breast fibroepithelial tumours, and are frequently found in chronic lymphocytic leukaemia (CLL). MED12 mutations have been previously linked to aberrant Cyclin C-CDK8 kinase activity, but the exact oncogenic function in CLL is unknown. Here, we characterized MED12 mutations in CLL and identified recurrent mutations in 13 out of 188 CLL patients (6·9%), which clustered in the N-terminus. MED12 mutations were associated with unmutated IGHV (P = 0·024). Protein analysis of NOTCH1 in primary CLL samples revealed increased levels of NOTCH1 intracellular domain (NICD), the active form of NOTCH1, in the context of MED12 mutations. We found evidence that NICD is the target of Cyclin C-CDK8 kinase using a specific CDK8 inhibitor. In line with these findings, MED12 mutations were mutually exclusive to mutations in NOTCH1 in CLL, based on a meta-analysis of 1429 CLL patients (P = 0·011). Our results suggest that MED12 mutations may contribute to CLL pathogenesis by activating NOTCH signalling.
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000130928 650_7 $$2NLM Chemicals$$aMED12 protein, human
000130928 650_7 $$2NLM Chemicals$$aMediator Complex
000130928 650_7 $$2NLM Chemicals$$aNOTCH1 protein, human
000130928 650_7 $$2NLM Chemicals$$aReceptor, Notch1
000130928 7001_ $$0P:(DE-HGF)0$$aSłabicki, Mikołaj$$b1
000130928 7001_ $$00000-0002-7893-401X$$aSellner, Leopold$$b2
000130928 7001_ $$0P:(DE-He78)6333b389d0abc96ef7f2f6e049a8f8c4$$aDietrich, Sascha$$b3$$udkfz
000130928 7001_ $$0P:(DE-He78)ca03e7517472097f49f822f5d6b0056f$$aLiu, Xiyang$$b4$$udkfz
000130928 7001_ $$0P:(DE-He78)7f506158c27b5827cd9021cd3dad37c8$$aJethwa, Alexander$$b5$$udkfz
000130928 7001_ $$0P:(DE-He78)c9be4ab60d1090c3d315a2ca6905e9ea$$aHüllein, Jennifer$$b6$$udkfz
000130928 7001_ $$0P:(DE-He78)e8feda17d03b95bda3e8717e79dc07b8$$aWalther, Tatjana$$b7$$udkfz
000130928 7001_ $$0P:(DE-He78)dafca537433ee26708b96d89aba38d29$$aWagner, Lena$$b8$$udkfz
000130928 7001_ $$0P:(DE-He78)c16f26d78779ca1c53b6939e7a5ce788$$aHuang, Zhiqin$$b9$$udkfz
000130928 7001_ $$0P:(DE-He78)1beba8f953e7ae7e96e8d3e9a48f10f7$$aZapatka, Marc$$b10$$udkfz
000130928 7001_ $$0P:(DE-He78)f3d5f16b49eb47520def635be98d5576$$aZenz, Thorsten$$b11$$eLast author$$udkfz
000130928 773__ $$0PERI:(DE-600)1475751-5$$a10.1111/bjh.14869$$gVol. 179, no. 3, p. 421 - 429$$n3$$p421 - 429$$tBritish journal of haematology$$v179$$x0007-1048$$y2017
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