Clinical Research Papers:

Somatic MED12 mutations are associated with poor prognosis markers in chronic lymphocytic leukemia

Kati Kämpjärvi _, Tiina M. Järvinen, Tuomas Heikkinen, Amy S. Ruppert, Leigha Senter, Kevin W. Hoag, Olli Dufva, Mika Kontro, Laura Rassenti, Erin Hertlein, Thomas J. Kipps, Kimmo Porkka, John C. Byrd, Albert de la Chapelle and Pia Vahteristo

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Oncotarget. 2015; 6:1884-1888. https://doi.org/10.18632/oncotarget.2753

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Kati Kämpjärvi1,*, Tiina M. Järvinen2,*, Tuomas Heikkinen1, Amy S. Ruppert3, Leigha Senter2, Kevin W. Hoag2, Olli Dufva1, Mika Kontro4, Laura Rassenti5, Erin Hertlein3, Thomas J. Kipps5, Kimmo Porkka4, John C. Byrd3, Albert de la Chapelle2, Pia Vahteristo1

1Department of Medical Genetics and Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland

2Department of Molecular Virology, Immunology and Medical Genetics, Division of Human Cancer Genetics, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA

3Department of Internal Medicine, Division of Hematology, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA

4Hematology Research Unit Helsinki, Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland

5Moores University of California-San Diego Cancer Center, University of California San Diego, CA, USA

*These authors have contributed equally to this work

Correspondence to:

Pia Vahteristo, e-mail: [email protected]

Keywords: Chronic lymphocytic leukemia, MED12, somatic mutation, cancer genetics, prognosis

Received: October 01, 2014     Accepted: November 15, 2014     Published: February 24, 2015


Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. We performed systematic database search and identified highly specific MED12 mutations in CLL patients. To study this further, we collected three independent sample series comprising over 700 CLL samples and screened MED12 exons 1 and 2 by direct sequencing. Mutations were identified at significant frequency in all three series with a combined mutation frequency of 5.2% (37/709). Positive mutation status was found to be associated with unmutated IGHV and ZAP70 expression, which are well-known poor prognosis markers in CLL. Our results recognize CLL as the first extrauterine cancer type where 5’terminus of MED12 is mutated at significant frequency. Functional analyses have shown that these mutations lead to dissociation of Cyclin C-CDK8/19 from the core Mediator and to the loss of Mediator-associated CDK kinase activity. Additional studies on the role of MED12 mutation status as a putative prognostic factor as well as mutations’ exact tumorigenic mechanism in CLL are warranted.

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