A research team at the University of Wisconsin Carbone Cancer Center has found a new tumor-causing mechanism that contributes to the development of the most common form of non-Hodgkin lymphoma.
Diffuse large B-cell lymphoma (DLBCL) originates from a B lymphocyte (B cell). Receptors on B cells send signals that direct the production of antibodies required for clearing viral or bacterial infections. DLBCL currently has a cure rate of less than 50 percent.
During normal immune responses, B-cell receptor signaling is tightly regulated and only occurs during a short window of time. In DLBCL, B-cell receptor signaling is unregulated, driving tumor formation, explained Lixin Rui, PhD, assistant professor of medicine at the UW School of Medicine and Public Health.
“We discovered that the B-cell receptor signaling controls the expression of protein arginine methyltransferase 5 (PRMT5), a gene encoding an enzyme that modifies proteins to regulate gene expression in a cell,” he said. “Interestingly, the activity of this enzyme is required for maintaining the B-cell signaling and therefore promotes cancer cell growth.”
Rui leads a research group that probes oncogenic signaling pathways contributing to lymphoma cell survival and proliferation.
The PRMT5 study, which was conducted by Fen Zhu, a graduate student in Rui’s laboratory, was recently published in the journal Leukemia.
Using human-derived DLBCL cell lines in cell culture and mouse models of the cancer, researchers tested the role of PRMT5 using genetic and pharmacological approaches. Zhu found that the expression of PRMT5 promotes the survival and proliferation of lymphoma cells in DLBCL, making PRMT5 an attractive potential therapeutic target. Further, targeting PRMT5 in lab-grown cells with a small molecule inhibitor reduces the survival and proliferation of cancer cells.
Genomic and biochemical studies by the team allowed them to identify molecular pathways involved in this process, indicating that PRMT5 promotes cell cycle progression. It also activates PI3K-AKT signaling, another proliferation pathway commonly activated in cancer cells. Co-targeting both PRMT5 and AKT by their specific inhibitors is lethal to DLBCL cell lines and primary cancer cells, explained Rui.
The anti-tumor effect of the PRMT5 inhibitor and the AKT inhibitor in DLBCL was confirmed in animal studies by Dr. Christian Capitini’s research group at the UW School of Medicine and Public Health and Dr. Michael Wang’s research team at MD Anderson Cancer Center.
Currently, Rui is working with UW colleague Vaishalee Kenkre, MD, assistant professor of medicine, to seek the possibility of a clinical trial using the PRMT5 inhibitor in diffuse large B-cell lymphoma.
The study was supported by funding from the National Cancer Institute R01 grant and the UW-Madison Forward Lymphoma Fund.