Selective expression of the transcription elongation factor ELL3 in B cells prior to ELL2 drives proliferation and survival

摘要

Highlights ? The transcriptional elongation factor ELL3 is up-regulated in activated B cells. ? Two ELL family members are non-concurrently expressed at specific B cell stages. ? The expression of ELL3 precedes expression of ELL2 during B cell differentiation. ? ELL3 plays a critical role in proliferation and survival of B cell models. ? PRDM1 (Blimp-1) silences expression of ELL3 in plasma cells. Abstract B cell activation is dependent on a large increase in transcriptional output followed by focused expression on secreted immunoglobulin as the cell transitions to an antibody producing plasma cell. The rapid transcriptional induction is facilitated by the release of poised RNA pol II into productive elongation through assembly of the super elongation complex (SEC). We report that a SEC component, the Eleven -nineteen Lysine-rich leukemia (ELL) family member 3 (ELL3) is dynamically up-regulated in mature and activated human B cells followed by suppression as B cells transition to plasma cells in part mediated by the transcription repressor PRDM1. Burkitt’s lymphoma and a sub-set of Diffuse Large B cell lymphoma cell lines abundantly express ELL3. Depletion of ELL3 in the germinal center derived lymphomas results in severe disruption of DNA replication and cell division along with increased DNA damage and cell death. This restricted utilization and survival dependence reveal a key step in B cell activation and indicate a potential therapeutic target against B cell lymphoma’s with a germinal center origin.