Mechanisms Behind EBV-Induced B Cell Growth Transformation Revealed

B cells, also known as B lymphocytes, play a crucial role in the immune system. However, when healthy B cells are infected with the Epstein-Barr virus (EBV), they undergo growth transformation, a process that immortalizes B cells, leading to their uncontrolled proliferation. The induction of immortalized B cells is the first step in the development of posttransplant lymphoproliferative disorder (PTLD), which can evolve to lymphoma and other lymphoproliferative disorders. The molecular mechanisms behind EBV-induced B cell growth transformation had been a mystery until a recent study conducted by researchers at Fujita Health University shed light on the process.

Published in Microbiology Spectrum, the study utilized primary B cells from healthy donors instead of cell lines to monitor the step-by-step growth transformation following EBV infection. As early as two days after infection, the morphology of B cells showed significant alterations. An enlargement of the nucleolus was observed, along with an increase in the number of nucleoli. Interestingly, nucleolar enlargement was followed by an enlargement of both—the nuclei and the cells.

To understand the transcriptional changes that occurred in infected B cells, RNA sequencing was performed. Among the genes showing significantly altered expression levels, one named IMPDH2 stood out, as it had previously been linked to similar morphological changes in glioblastoma. Careful analysis showed that the levels of the IMPDH2 peaked two days after infection—coinciding with the timing of nucleolar enlargement. 

Further investigation showed that IMPDH2 induction and nucleolar enlargement could be triggered when primary B cells were activated using inflammatory signals, even in the absence of EBV infection. To confirm IMPDH2's role, the researchers inhibited it using silencer RNAs and the drug mycophenolic acid (MPA), which prevented B cell growth transformation after EBV infection. The study also found that EBV induces IMPDH2 expression via EBNA2-dependent mechanisms, along with the involvement of cellular transcription factor MYC.

To highlight the clinical significance of their findings, the team examined whether the drug mycophenolate mofetil (MMF) could prevent B cell transformation and PTLD. They found that the administration of MMF in a mouse xenograft model led to improved survival and reduced splenomegaly (enlargement of the spleen, indicating reduced B cell proliferation). These observations confirmed that the use of MMF can inhibit PTLD development.