IRF4: Immunity. Malignancy! Therapy?

Myeloma cells are addicted to IRF4 expression such that even a modest decrease in IRF4 levels leads to cell death. IRF4 (green) controls an aberrant gene expression program in MM cells that fuses and expands the gene expression programs of activated B cells and PCs and directly controls the expression genes critical for cell cycle control, transcriptional regulation, plasma cell differentiation, and membrane biogenesis. There are several points at which IRF4 activity might be interrupted in a therapeutically advantageous manner (X). X1, target the signals activating (star) IRF4 expression, such as NF-kB. X2, target the known regulators of IRF4 expression in MM, MYC and IRF4 itself. X3, target the ability of IRF4 to interact with a binding partner (blue), thereby preventing IRF4 binding to target DNA sequences. X4, target putative post-translational modifications of IRF4 that may alter its ability to bind DNA or activate transcription. X5, target critical pathways downstream of IRF4. For example, the isoprenoid/cholesterol biosynthesis pathway can be targeted by drugs such as statins or farnesylation inhibitors. Any reduction in IRF4 activity will result in cell ‘death by a thousand cuts’ due to metabolic collapse following the downregulation of several key pathways.

Publication

IRF4: Immunity. Malignancy! Therapy?. () Arthur L. Shaffer, et al. Clin Cancer Res. ;15(9):2954-2961. Figure: F2. All organisms Homo sapiens Mus musculus Drosophila melanogaster

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