Loss of BCL7A permits IRF4 transcriptional activity and cellular growth in multiple myeloma

ABSTRACT: Multiple myeloma (MM) is a complex hematological malignancy characterized by genomic changes and transcriptomic dysregulation. Initial exome sequencing approaches have failed to identify any single, frequent (>25%) mutation in the coding genome. However, using whole-genome sequencing, we found that one of the genomic regions most frequently mutated (62% of the patients with MM) was the 5' untranslated region and/or intron 1 of the BCL7A gene. RNA-sequencing data from a large cohort suggest a loss of BCL7A expression in a large majority of patients with MM as compared with normal plasma cells. BCL7A loss of function in a panel of MM cell lines led to a highly proliferative phenotype in vitro and in vivo, whereas its ectopic expression significantly reduced cell viability, suggesting a tumor suppressor function for BCL7A in MM. We studied the cellular and molecular effects of BCL7A loss and observed that it endows myeloma cells with proliferative potential in cooperation with the plasma cell-defining transcription factor IRF4. BCL7A is involved in a direct protein-protein interaction with IRF4, limiting its DNA-binding activity. Loss of BCL7A thus enhances the expression of IRF4-associated cytokines and reduces mitochondrial metabolism and reactive oxygen species levels. Our study therefore suggests that BCL7A loss provides the necessary molecular change to allow IRF4-mediated transcriptional activity and MM cell growth and survival.