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, 15 (9), 2954-61

IRF4: Immunity. Malignancy! Therapy?


IRF4: Immunity. Malignancy! Therapy?

Arthur L Shaffer et al. Clin Cancer Res.


IRF4, a member of the Interferon Regulatory Factor (IRF) family of transcription factors, is expressed in cells of the immune system, where it transduces signals from various receptors to activate or repress gene expression. IRF4 expression is a key regulator of several steps in lymphoid-, myeloid-, and dendritic-cell differentiation, including the differentiation of mature B cells into antibody-secreting plasma cells. IRF4 expression is also associated with many lymphoid malignancies, with recent evidence pointing to an essential role in multiple myeloma, a malignancy of plasma cells. Interference with IRF4 expression is lethal to multiple myeloma cells, irrespective of their genetic etiology, making IRF4 an "Achilles' heel" that may be exploited therapeutically.


Figure 1
Figure 1. IRF4 regulatory networks in B cell differentiation and malignancy
IRF4 lies at the center of regulatory networks that function at several stages of B cell differentiation and drive malignancy. A. In resting mature B cells IRF4 levels are low or absent due to MITF repression of the IRF4 gene. B. IRF4 expression is induced by BCR, CD40, and cytokine stimulation via NF-kB and STAT factors in activated B cells, and MITF repression is relieved. IRF4 acutely drives MYC and PRDM1 expression, as well as feeding back to drive its own expression. This results in a burst of cell division (driven by MYC) and subsequent differentiation of a proportion of the cells into short-lived Ig-secretors (driven by PRDM1). C. Germinal center B cells (GC) express IRF8 while IRF4 levels are low due to lack of NF-kB activation as well as repression of IRF4 by MITF. This allows the expression of the key GC regulator, BCL6, which in turn represses PRDM1, the plasma cell master regulator, locking the cells into the GC phenotype. Lack of IRF4 also contributes to the absence of MYC expression in GC B cells. D. As B cells exit the GC, they may differentiate to PCs. IRF4 expression, initiated by activation stimuli, becomes activation-independent via IRF4 auto-induction. IRF4 represses the GC regulator BCL6 and directly induces expression of the PC regulator PRDM1. PRDM1 also directly or indirectly represses BCL6 expression, committing cells to a PC fate. In addition, PRDM1 directly represses MYC, leading to the non-dividing, Ig-secreting phenotype of terminally differentiated PCs. E. In multiple myeloma (MM), the malignant counterpart of normal PCs, IRF4 represses BCL6 and promotes PRDM1 expression as in PCs, but both MYC and IRF4 are over-expressed. For unknown reasons, MYC is not repressed by PRDM1 in MM, leading to a positive feedback loop between IRF4 and MYC as seen in activated B cells. Thus MM fuses the activated B cell and PC IRF4-driven gene expression programs, leading to malignant transformation and cell division. Solid black arrows/lines – active regulation; Gray arrows/lines – inactive regulation; solid letters – active factor; open letters – inactive factor.
Figure 2
Figure 2. Disrupting IRF4 Function in Myeloma
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.

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