IRF4 negatively regulates proliferation of germinal center B cell-derived Burkitt's lymphoma cell lines and induces differentiation toward plasma cells

Abstract

To investigate the roles of interferon regulatory factor 4 (IRF4) in B-cell development, we established germinal center B cell-derived Burkitt's lymphoma cell lines that exogenously express IRF4. Daudi-IRF4 expressed IRF4 in the presence of doxycycline (inducible expression), and Raji-IRF4 constitutively expressed an IRF4-estrogen receptor chimeric protein, which was activated by 4-hydroxytamoxifen. Expression or activation of IRF4 resulted in growth inhibition accompanied by accumulation of cells in G0/G1. Upregulation of the plasma cell markers CD38 and CD138 and downregulation of the germinal center cell marker B-cell lymphoma 6 (BCL6) were also observed. Furthermore, mRNAs for BCL6 and paired box gene 5 (PAX5) were decreased and those for B-lymphocyte-induced maturation protein-1 (BLIMP1)/PR domain containing 1 (PRDM1) and X-box binding protein 1 (XBP1) were increased, which corresponds to the characteristic changes in transcription factor expression in B cells differentiating toward plasma cells. Impairment in proliferation and differentiation toward plasma cells induced by IRF4 were not inhibited by enforced expression of BCL6. These results suggest that IRF4 inhibits cell cycle progression of germinal center B cell-derived Burkitt's lymphoma cells and induces terminal differentiation toward plasma cells through mechanisms independent of BCL6 downregulation.