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MED 12 mutations and NOTCH signalling in chronic lymphocytic leukaemia
Author(s) -
Wu Bian,
Słabicki Mikołaj,
Sellner Leopold,
Dietrich Sascha,
Liu Xiyang,
Jethwa Alexander,
Hüllein Jennifer,
Walther Tatjana,
Wagner Lena,
Huang Zhiqin,
Zapatka Marc,
Zenz Thorsten
Publication year - 2017
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14869
Subject(s) - ighv@ , chronic lymphocytic leukemia , mutation , biology , cancer research , notch signaling pathway , genetics , microbiology and biotechnology , gene , leukemia
Summary Mutations in the N‐terminus of MED 12 protein occur at high frequency in uterine leiomyomas and breast fibroepithelial tumours, and are frequently found in chronic lymphocytic leukaemia ( CLL ). MED 12 mutations have been previously linked to aberrant Cyclin C‐ CDK 8 kinase activity, but the exact oncogenic function in CLL is unknown. Here, we characterized MED 12 mutations in CLL and identified recurrent mutations in 13 out of 188 CLL patients (6·9%), which clustered in the N‐terminus. MED 12 mutations were associated with unmutated IGHV ( P = 0·024). Protein analysis of NOTCH 1 in primary CLL samples revealed increased levels of NOTCH 1 intracellular domain ( NICD ), the active form of NOTCH 1, in the context of MED 12 mutations. We found evidence that NICD is the target of Cyclin C‐ CDK 8 kinase using a specific CDK 8 inhibitor. In line with these findings, MED 12 mutations were mutually exclusive to mutations in NOTCH 1 in CLL , based on a meta‐analysis of 1429 CLL patients ( P = 0·011). Our results suggest that MED 12 mutations may contribute to CLL pathogenesis by activating NOTCH signalling.