1. Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
2. Biometric Research Branch, National Cancer Institute, Rockville, Maryland 20892, USA
3. Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, Maryland 20892, USA
4. Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72212, USA

Correspondence to: Louis M. Staudt¹ Correspondence and requests for materials should be addressed to L.M.S. (Email: lstaudt@mail.nih.gov).

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 cells^{1, 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 translocations^{4, 5}. Moreover, the malignant clone can sustain multiple oncogenic lesions, accumulating genetic damage as the disease progresses^{6, 7}. Current therapies for myeloma can extend survival but are not curative^{8, 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.

1. Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
2. Biometric Research Branch, National Cancer Institute, Rockville, Maryland 20892, USA
3. Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, Maryland 20892, USA
4. Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72212, USA

Correspondence to: Louis M. Staudt¹ Correspondence and requests for materials should be addressed to L.M.S. (Email: lstaudt@mail.nih.gov).

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