IRF4 addiction in multiple myeloma

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Abstract
An RNA interference scan for genes linked to the proliferation of myeloma cell lines as possible drug targets has identified the transcription factor factor IRF4, needed for lymphocyte activation and plasma cell differentiation in normal cells, as a master regulator of multiple myeloma. Strikingly, myeloma cells are completely dependent on IRF4, despite that fact that most do not harbour mutations, translocations or amplifications of the IRF4 locus. In cancer cells, IRF4 controls a different network of genes — including the MYC oncogene — than in normal plasma cells or activated B cells. IRF4 dependency in myeloma is an example of 'non-oncogene addiction', where cancer cells depend on a normal cellular protein for proliferation and/or survival. The transcription factor IRF4, required for lymphocyte activation and plasma cell differentiation, is shown here to be a master regulator of multiple myeloma. It controls a different network of genes in the cancer than it does in normal plasma cells or activated B cells. 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.