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The transcription factor IRF4 represses pro-apoptotic BMF and BIM to licence Multiple Myeloma survival

ABSTRACT: The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for the survival of the plasma cell malignancy multiple myeloma (MM), although the mechanism by which this is achieved remains unknown. Here we have explored the genetic basis for IRF4 addiction through CRISPR-Cas9 genetic ablation of IRF4 across several MM cells lines. We report that IRF4 loss uniformly resulted in the upregulation of two related pro-apoptotic proteins belonging to the BH3-only subgroup of the BCL2 family: BCL2 modifying factor (BMF) and BCL2 interacting mediator of cell death (BIM). Direct IRF4 binding was identified in the proximal promoter region of both genes. Remarkably, genetic ablation of BMF alone or in combination with BIM largely prevented the cell death that follows IRF4 inactivation, establishing that IRF4 maintains MM survival through the direct transcriptional repression of BMF and BIM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148984 | GEO | 2022/12/22

REPOSITORIES: GEO

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