IRF4 addiction in multiple myeloma.
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. Multiple myeloma, a malignancy of plasma cells, has a complex molecular aetiology with several subgroups defined by gene expression profiling and recurrent chromosomal translocations. Moreover, the malignant clone can sustain multiple oncogenic lesions, accumulating genetic damage as the disease progresses. Current therapies for myeloma can extend survival but are not curative. 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.
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Arthur L
AL
Shaffer
N C Tolga
NC
Emre
Laurence
L
Lamy
Vu N
VN
Ngo
George
G
Wright
Wenming
W
Xiao
John
J
Powell
Sandeep
S
Dave
Xin
X
Yu
Hong
H
Zhao
Yuxin
Y
Zeng
Bangzheng
B
Chen
Joshua
J
Epstein
Louis M
LM
Staudt
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D015533:Transcriptional Activation; D000099218:Interferon Regulatory Factor-4
D050835:Interferon Regulatory Factors; D016271:Proto-Oncogene Proteins c-myc; D000099218:Interferon Regulatory Factor-4