MED12 mutations and NOTCH signalling in chronic lymphocytic leukaemia

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.

The emerging role of mediator complex subunit 12 in tumorigenesis and response to chemotherapeutics

“…Because NOTCH1 intracellular domain is a substrate of CycC‐CDK8 kinase, this finding is congruent with the N‐terminal MED12 mutations affecting CDK8 kinase activity and NOTCH1 activation. Therefore, mutating MED12 appears to be an alternative route for the activation of NOTCH signaling in CLL pathogenesis …”

“…Identifying early disease‐driven mutations will help to stratify patients for personalized treatments . In chronic lymphocytic leukemia (CLL), N‐terminal MED12 mutations were identified with a frequency of 5.2% (37 of 709 patients), 6.9% (12 of 188 patients), and 8.8% (10 110 patients) in 3 independent studies . NOTCH signaling is known to regulate differentiation and tumorigenesis in multiple cancers, including CLL .…”

“…18,19 In chronic lymphocytic leukemia (CLL), N-terminal MED12 mutations were identified with a frequency of 5.2% (37 of 709 patients), 6.9% (12 of 188 patients), and 8.8% (10 110 patients) in 3 independent studies. 20,21 NOTCH signaling is known to regulate differentiation Cancer March 1, 2020 and tumorigenesis in multiple cancers, including CLL. 22 Although the occurrence of MED12 and NOTCH1 mutations in CLL are mutually exclusive, NOTCH1 intracellular domain, the active form of NOTCH1, was elevated in CLL samples harboring MED12 mutations.…”

“…Therefore, mutating MED12 appears to be an alternative route for the activation of NOTCH signaling in CLL pathogenesis. 19,21 MED12 mutations have also been identified in colorectal cancer (CRC), gastric cancer, and nonanaplastic thyroid cancer by next-generation sequencing. An MED12 exon 2 mutation was observed in 389 patients with colon cancer (0.3%).…”

Tumor Suppressors in Chronic Lymphocytic Leukemia: From Lost Partners to Active Targets

“…F-box/WD repeat-containing protein 7, FBXW7, mediator complex subunit 12 (MED12), and spen family transcriptional repressor (SPEN), three tumor suppressors associated with the regulation of the NOTCH1 pathway, were also identified as being mutated with low frequency in CLL. In particular, FBXW7 and MED12 mutations prevent proteasomal degradation of NOTCH1, whereas SPEN interferes with NOTCH1 signaling [45][46][47]. Interestingly, the homozygous deletion of the SPEN gene was found at RS diagnosis [48].…”