The role of activation-induced cytidine deaminase (AID) mediated DNA damage in the pathogenesis of Burkitt's Lymphoma

• Applicant: Dr. Till Schoofs
• Subject Area: Hematology, Oncology ; Immunology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258438392

Secondary diversification of the immunoglobulin repertoire through somatic hypermutation (SHM) and class switch recombination (CSR) is crucial for generating high affinity antibody responses. During SHM point mutations are introduced into the variable region of the antibody, while a deletional recombination reaction during CSR helps to pair a particular variable region to a new constant region thereby generating a different antibody class. SHM and CSR occur in germinal center (GC) B-cells and are both mediated by activation-induced cytidine deaminase (AID), an enzyme that is specifically expressed upon activation of B-cells in the GC. The enzyme AID works by deaminating cytosine residues in actively transcribed genes and has been shown to drive mutations in immunoglobulin (Ig) genes as well as in a spectrum of non-Ig genes, including oncogenes such as c-myc. AID-induced mutations can be processed by different repair pathways, sometimes yielding DNA double-strand breaks (DSBs) which are an obligate intermediate during the process of CSR. These DSBs can be repaired locally, but can also be recombined to yield chromosome translocations, which are common findings in leukemias and lymphomas.One such translocation whose occurrence has been linked to AID in vitro is the t(8;14) which is found in 80% of cases of Burkitt's lymphoma. The incidence of Burkitt's lymphoma is strongly associated with chronic infectious stimuli, in particular with Epstein-Barr-Virus (EBV) and malaria (Plasmodium spp.) infections. These chronic infectious stimuli are known to result in chronic B-cell stimulation and chronic expression of AID in GCs. Potentially, this chronic expression of AID might be responsible for lymphomagenesis by mediating disease-initiating translocations. However, little is so far known about the mutations caused by AID expression in vivo. In the course of this project, we, therefore, want to investigate whether AID mediated mutations drive tumor formation in B-cells in vivo. For this purpose, a mouse model of chronic malaria infection using Plasmodium chabaudi has recently been established. In the context of genetic loss of p53, these mice develop mature B-cell lymphomas. Using this mouse model and novel deep sequencing approaches, we are going to characterize the AID-mediated mutational landscape in primary B-cells of mice that are chronically infected with malaria. In comparing this landscape with the mutational landscape found in mature lymphomas arising in these chronically infected mice, we are going to determine the contribution of AID towards lymphoma formation in vivo.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Michel C. Nussenzweig, Ph.D.