Plasma cell gene expression depends on ELL2 (HEM2P.271)

Abstract

Abstract ELL2, the eleven-nineteen lysine rich leukemia gene, a transcription elongation factor, has been found to play vital roles in Igh mRNA production, myeloma cell survival, and in HIV tar:tat mediated viral RNA transcription. We previously showed that ELL2 is responsible for Igh mRNA being both alternatively processed to the secretory-specific form and increased in its abundance, leading to high levels of secreted Ig protein and a robust immune response. ELL2 associates with pTEFb in a super elongation complex. We made conditional knockouts of ELL2 in mouse B cells using loxp/ CD19 cre. The splenic B cell populations of T3 and mature plasma cells in the whole mouse are reduced in the knockouts. The ELL2 cKO results in decreased serum Ig levels and severe reduction in antigen specific responses against NP-ficoll and NP-KLH. Recall responses are also impaired. LPS stimulation of splenic B cells shows decreased maturation to B220loCD138+ plasma cells with the expression of IRE1, XBP-1 spliced form, and cyclin B2 significantly lower in the cKO than LPS stimulated WT mice. The processing of the Igh mRNA to the secretory-specific form is suppressed in the conditional ELL2 knockouts with a compensatory increase in Igh membrane mRNA. Production of the unfolded protein response is thus impaired. Analysis of the ELL2 knockouts may lend insight into the relationships between Ig secretion, cell growth and the unfolded protein response in plasmablasts and long term plasma cells.