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@ARTICLE{Wu:130928,
author = {B. Wu$^*$ and M. Słabicki$^*$ and L. Sellner$^*$ and S.
Dietrich$^*$ and X. Liu$^*$ and A. Jethwa$^*$ and J.
Hüllein$^*$ and T. Walther$^*$ and L. Wagner$^*$ and Z.
Huang$^*$ and M. Zapatka$^*$ and T. Zenz$^*$},
title = {{MED}12 mutations and {NOTCH} signalling in chronic
lymphocytic leukaemia.},
journal = {British journal of haematology},
volume = {179},
number = {3},
issn = {0007-1048},
address = {Oxford [u.a.]},
publisher = {Wiley-Blackwell55962},
reportid = {DKFZ-2017-06004},
pages = {421 - 429},
year = {2017},
abstract = {Mutations 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.},
keywords = {MED12 protein, human (NLM Chemicals) / Mediator Complex
(NLM Chemicals) / NOTCH1 protein, human (NLM Chemicals) /
Receptor, Notch1 (NLM Chemicals)},
cin = {G100 / B060 / G250},
ddc = {610},
cid = {I:(DE-He78)G100-20160331 / I:(DE-He78)B060-20160331 /
I:(DE-He78)G250-20160331},
pnm = {317 - Translational cancer research (POF3-317)},
pid = {G:(DE-HGF)POF3-317},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:28771672},
doi = {10.1111/bjh.14869},
url = {https://inrepo02.dkfz.de/record/130928},
}