Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

Abstract

The transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1) has crucial roles in the control of plasma cell differentiation and in maintaining survival of plasma cells. However, how Blimp-1 ensures the survival of plasma cell malignancy, multiple myeloma (MM), has remained elusive. Here we identified Aiolos, an anti-apoptotic transcription factor of MM cells, as a Blimp-1-interacting protein by mass spectrometry. ChIP coupled with DNA microarray was used to profile the global binding of Aiolos and Blimp-1 to endogenous targets in MM cells, which revealed their co-binding to a large number of genes, including apoptosis-related genes. Accordingly, Blimp-1 and Aiolos regulate similar transcriptomes in MM cells. Analysis of the binding motifs for Blimp-1 and Aiolos uncovered a partial motif that was similar across sites for both proteins. Aiolos promotes the binding of Blimp-1 to target genes and thereby enhances Blimp-1-dependent transcriptional repression. Furthermore, treatment with an anti-MM agent, lenalidomide, caused ubiquitination and proteasomal degradation of Blimp-1, leading to the de-repression of a new Blimp-1 direct target, CULLIN 4A (CUL4A), and reduced Aiolos levels. Accordingly, lenalidomide-induced cell death was partially rescued by reintroduction of Blimp-1 or knockdown of CUL4A. Thus, we demonstrated the functional impacts and underlying mechanisms of the interaction between Aiolos and Blimp-1 in maintaining MM cell survival. We also showed that interruption of Blimp-1/Aiolos regulatory pathways contributes to lenalidomide-mediated anti-MM activity.

PRDI-BF1 and PRDI-BF1β isoform expressions correlate with disease status in multiple myeloma patients

“…in particular, PRDI-BF1 is required for XBP-1 induction, a transcriptional activator necessary for plasma cell survival because reduction levels of activated XBP1 determined by proteasome inhibitors causes rapidly cell apoptosis. 7 PRDI-BF1 and the PRDI-BF1β can be considered a crucial point for understanding efficacy and limits of many new drugs used in MM.…”

“…Accordingly, lenalidomide-induced cell death was partially rescued by reintroduction of PRDI-BF1. 5 , 7 Anyway, no data are still available about the different expressions of PRDI-BF1 and its isoform beta during the clinical evolution and the management of Myeloma patients.…”

IRF4 in multiple myeloma—Biology, disease and therapeutic target

“…Conery et al The MM specific IRF4 aberrant downstream transcriptional network could also represent a valid target for inhibition. Previous studies reported that knockdown of Blimp1 by short hairpin RNA causes apoptosis in MM cells [68] and that the interaction between Ailos and Blimp1 plays an important role in MM cells survival, probably through the collaborative down-regulation of proapoptotic genes [69]. Moreover, treatment with IMiD lenalidomide caused proteasomal degradation of Blimp1 and reduced Aiolos levels leading to apoptosis of MM cells [69].…”

Zinc finger–IRF composite elements bound by Ikaros/IRF4 complexes function as gene repression in plasma cell

“…The regulatory motif of IRF4 overlaps with that of Blimp-1, and Aiolos contributes to Blimp-1 function. 39 Thus, each Ikaros family member likely involves nonoverlapping roles in IRF4 and Blimp-1-dependent PC differentiation.…”