Role of JMJD3 in B cell development and lymphoid neoplasia

• Applicant: Dr. Tobias Berg
• Subject Area: Hematology, Oncology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 281716908

Multiple genetic aberrations involving epigenetic regulators have recently been identified in B cell lymphoma. This points towards an important role of epigenetic regulation in B cell biology and malignant transformation. The polycomb-repressive complex 2 (PRC2) is often affected by mutations, in particular its catalytic component EZH2. This complex regulates the trimethylation of H3K27. EZH2 and thereby the trimethylation of H3K27me3 has also been shown to be critically involved in B cell development and the germinal-center reaction. The applicant has previously been involved in work demonstrating that the identified EZH2 mutations lead to a gain-of-function and has shown in mouse model that these mutations collaborate with Eµ-Myc to induce rapid lymphoma development. The trimethylation of histone H3K27 is also regulated by two specific histone demethylases: JMJD3 and UTX. JMJD3 has previously shown to be downregulated in a subgroup of diffuse large B cell lymphomas. As novel inhibitors will allow us to specifically target H3K27 trimethylation, it appears of great interest to investigate the role of the different regulators that influence this epigenetic modification.We hypothesize that JMJD3 also plays a role in B cell development and in the germinal-center reaction and that a loss of JMJD3 leads to lymphoma development. Our objective is to make use of a conditional Jmjd3 knockout model to investigate the role of Jmjd3 in normal and malignant B lymphopoiesis and determine the consequences of a loss of JMJD3 on the epigenome and gene expression as well as investigate the degree of overlap between genes targeted by PRC2 and JMJD3.In detail, we will pursue the following aims: Aim 1: To investigate the role of Jmjd3 in B cell development and analyze its function in the germinal-center reactionAim 2: To study the impact of Jmjd3 on lymphoma developmentAim 3: To analyze the molecular consequences of a loss of Jmjd3 in the B cell compartment on gene expression and epigenome

• DFG Programme: Research Grants
• International Connection: Canada
• Cooperation Partners: Professor Dr. Keith Humphries; Professor Dr. Marco Marra