Epstein-Barr virus- and malaria-associated Burkitt’s lymphoma: AID/APOBEC enzymes as key molecules and future therapeutic targets?

Burkitt’s lymphoma (BL) is associated Epstein-Barr virus (EBV) and with Plasmodium falciparum malaria, but the underlying oncogenic mechanisms are still unclear. Preliminary results from the laboratory provide evidence that EBV and malaria induce the expression and activity AID/APOBEC enzymes, and that these enzymes can cause mutations that drives Burkitt’s lymphoma. In the proposed project, the aim is to confirm these preliminary findings and to identify key molecules in these processes. Furthermore, we plan to explore the application of AID/APOBEC inhibitors as potential drugs for future therapies that may be administered during acute EBV infection or malaria, with the aim to prevent the development of BL. First, the project will confirm that EBV up-regulates AID/APOBEC enzymes in B cells by infecting human B cells with EBV followed by analysis of AID/APOBEC enzyme expression enzymatic activity by qRT-PCR and deaminase activity assays, respectively. Preliminary data of our laboratory showed that malaria patients have increased AID/APOBEC levels in their B cells compared to healthy controls, suggesting that malaria can up-regulate AID/APOBEC enzymes. It will confirm this hypothesis by analyzing further patients and controls, and in functional assays, where we culture human B cells with vesicles from malaria-infected red blood cells, followed by analysis of AID/APOBEC enzymes expression and activity. To identify mechanisms and key molecules that mediate AID/APOBEC enzyme expression and activity, we will stimulate B cells with candidate molecules and block these molecules upon infecting B cells with EBV, and upon culturing B cells with vesicles from malaria-infected red blood cells. Last, we will evaluate whether these EBV- and malaria-induced enzymes can cause mutations that promotes BL by whole genome sequencing and analysis of mutational signatures characteristic for AID/APOBEC enzymes. Finally, we will assess whether these BL-associated mutations can be prevented by AID/APOBEC inhibitors when applied during infection with EBV or stimulation with Plasmodium falciparum. Such inhibitors targeting expression or mutagenic activity of AID/APOBEC enzymes may be administered during acute infection with EBV and acute malaria in order to prevent the mutations that causes Burkitt’s lymphoma. Since AID/APOBEC enzymes contribute to a wide range cancers, AID/APOBEC inhibitors may find a broad application in future cancer therapies.

Basic Science

Jul 2020 — Jun 2024

$67,124

Switzerland