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IRF4 addiction in multiple myeloma

Abstract

The transcription factor IRF4 (interferon regulatory factor 4) is required during an immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells1,2,3. Multiple myeloma, a malignancy of plasma cells, has a complex molecular aetiology with several subgroups defined by gene expression profiling and recurrent chromosomal translocations4,5. Moreover, the malignant clone can sustain multiple oncogenic lesions, accumulating genetic damage as the disease progresses6,7. Current therapies for myeloma can extend survival but are not curative8,9. Hence, new therapeutic strategies are needed that target molecular pathways shared by all subtypes of myeloma. Here we show, using a loss-of-function, RNA-interference-based genetic screen, that IRF4 inhibition is toxic to myeloma cell lines, regardless of transforming oncogenic mechanism. Gene expression profiling and genome-wide chromatin immunoprecipitation analysis uncovered an extensive network of IRF4 target genes and identified MYC as a direct target of IRF4 in activated B cells and myeloma. Unexpectedly, IRF4 was itself a direct target of MYC transactivation, generating an autoregulatory circuit in myeloma cells. Although IRF4 is not genetically altered in most myelomas, they are nonetheless addicted to an aberrant IRF4 regulatory network that fuses the gene expression programmes of normal plasma cells and activated B cells.

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Figure 1: IRF4 is required for myeloma cell survival.
Figure 2: IRF4 target genes in multiple myeloma.
Figure 3: MYC is a direct IRF4 target gene in myeloma and activated B cells.
Figure 4: IRF4 is a direct MYC target gene in myeloma and activated B cells.
Figure 5: Model of IRF4 control over B cell development and multiple myeloma oncogenesis.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data are deposited in the NCBI GEO database under accession numbers GSE8958, GSE9067 (gene expression) and GSE9367 (ChIP–CHIP).

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institute of Health (NIH), National Cancer Institute, Center for Cancer Research. Y.Z., B.C. and J.E. were supported by NCI grants CA97513 and CA113992. We wish to thank K. Meyer for her assistance with GEO submissions; D. Levens, J. Liu and H.-J. Chung for assistance with MYC ChIP assay design and the MYC promoter-GFP reporter construct; K. Ozato and L. Ramakrishna for IRF4-deficient mice; and M. Kuehl and members of the Staudt laboratory for their assistance and discussions.

Author Contributions Experimental design/discussion, A.L.S., V.N.N., J.E. and L.M.S.; preparation and performance of experiments, A.L.S, N.C.T.E., L.L., V.N.N., S.D., X.Y., H.Z., Y.Z. and B.C.; data analysis/interpretation, A.L.S., N.C.T.E., W.X., G.W., J.P., J.E. and L.M.S.; manuscript preparation, A.L.S. and L.M.S.

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Correspondence to Louis M. Staudt.

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Shaffer, A., Emre, N., Lamy, L. et al. IRF4 addiction in multiple myeloma. Nature 454, 226–231 (2008). https://doi.org/10.1038/nature07064

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