Abstract
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.
Highlights
Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in Western societies
746 samples from three independent sample series were included in the study
There is no obvious bias in the collection or characteristics of the sample series, which could explain the slightly higher mutation frequency in the CLL Research Consortium (CRC) series
Summary
Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in Western societies. The clinical course of patients with this disease is heterogeneous, ranging from highly indolent, which may never require therapy, to relatively aggressive, which may require therapy soon after diagnosis. CLL can be divided into two subclasses based on the occurrence of somatic hypermutation in the immunoglobulin heavy-chain variable (IGHV) genes. [1] The subclass with mutated IGHV genes (M-CLL) has an improved treatment-free and overall survival compared to the subclass with unmutated IGHV genes (U-CLL) [2, 3]. There is no curative drug therapy for CLL, but chemo-immunotherapy can significantly improve survival [4]. As the course of the disease is highly unpredictable, there is an urgent need to better elucidate the biology of CLL
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