Abstract Somatic mutations in exons 1 and 2 of the Mediator complex subunit 12 (MED12) have been identified in 70% of uterine leiomyomas, 7-20% of uterine leiomyosarcomas, 59% of breast fibroadenomas and 67% of breast phyllodes tumors. In addition to female hormone-dependent tumors we have recently found the same specific missense and small in-frame insertion and deletion mutations in approximately 5% of chronic lymphocytic leukemias (CLL). In CLL the presence of MED12 mutations was also associated with markers of poor prognosis (IgVH (-), Zap70 (+), and Zap70-methylation). The surprising finding of the same mutations in a completely different tumor type prompted us to further screen other hematological malignancies for MED12 mutations. We have thus far collected samples of 107 T-cell acute lymphoblastic leukemias (T-ALL), 21 large granular lymphocyte leukemias (LGL), 33 acute myeloid leukemias (AML), 154 diffuse large B cell lymphomas (DLBCL), and 6 six follicular lymphomas (FL). Also a set of 30 additional CLLs was collected. The MED12 mutation status was determined by direct Sanger sequencing of exons 1 and 2 of the gene. A c.107T>G, p.L36R mutation was found in a single DLBCL case and c.100-8T>A, p.E33_D34insPQ in one AML sample. A novel variant of uncertain significance, c.-3A>G, was detected on 5’UTR of one FL sample. One T-ALL patient harbored a nonsense mutation affecting the last codon of exon 1 c.97G>T, p.E33X. No mutations were identified in the LGL or CLL samples. We are also analyzing approximately 100 new AML samples and 100 multiple myeloma samples. MED12 mutations are present, in addition to CLL, also in other hematological malignancies. The frequency, however, seems to be low and, as the number of samples in the preliminary analysis is limited, screening of larger sample sets is needed. The c.107T>G, p.L36R and c.100-8T>A, p.E33_D34insPQ mutations have previously been detected recurrently in uterine leiomyomas and in CLL. Further studies are required for evaluation of the effects of c.-3A>G and c.97G>T, p.E33X mutations. The latter mutation affects the last codon of exon 1, which is also a mutational hotspot in CLL, with recurrent missense mutations. MED12 exon 1 and 2 missense mutations disrupt the interactions between the Mediator complex and Cyclin C and cause loss of CDK8 kinase activity. Studies to determine the impact of the c.97G>T, p.E33X mutation on MED12 function are ongoing. Citation Format: Tuomas Heikkinen, Kati Kämpjärvi, Sirpa Leppä, Peter Hokland, Heikki Kuusanmäki, Satu Mustjoki, Marjatta Sinisalo, Caroline Heckman, Mika Kontro, Pia Vahteristo. Somatic MED12 mutations in hematological malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1169.