IRF4 addiction in multiple myeloma
Open accessAbstract
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.
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Targeted degradation of IKZF1 and IKZF3 by iMiDs exerts a dual response in multiple myeloma: anti-proliferative effects via IRF4 destabilization and immune enhancement via increased cytokine production.
“the targeted degradation of iKZF1 and iKZF3 by iMiDs exerts a dual response in the treatment of multiple myeloma.First, the dependency of these cancers on iRF4 signaling is well-documented, making it unsurprising that the destabilization of iRF4, through the destruction of iKZF1 and iKZF3, would lead to anti-proliferative effects (Shaffer et al. 2008).Second, iKZF1 plays an important role in”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Shaffer et al. 2008
The cited passage (indexed as Abstract; page unavailable) shows that myeloma cell lines depend on IRF4 and that IRF4 knockdown kills them. It does not establish that iMiDs degrade IKZF1/IKZF3, destabilize IRF4, or produce the proposed anti-proliferative effect through that pathway. The citation appears before the citing text turns to its second, immune-related response, so cytokine production is not attributed to this source here. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIRF4 and c-Myc work together in a positive-feedback loop to drive gene expression profiles associated with myeloma progression.
“iRF4 and c-Myc work together in a positive-feedback loop to drive gene expression profiles associated with myeloma progression (Shaffer et al. 2008;Bjorklund et al. 2015).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Shaffer et al. 2008
The Abstract describes a positive regulatory loop in which IRF4 and MYC reinforce each other’s expression and an aberrant, malignancy-specific gene-expression program controlled by IRF4. It does not establish that this loop drives profiles specifically associated with myeloma progression, rather than myeloma more generally. (LLM, conf=0.85)
Experimental — accuracy not yet measured
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“…Morgan et al. 2012). iRF4 and c-Myc work together in a positive-feedback loop to drive gene expression profiles associated with myeloma progression (Shaffer et al. 2008; Bjorklund et al. 2015). iRF4-dependency is also a hallmark of other haematopoietic malignancies, including B cell lymphomas,…”
- Authors
- Shaffer, A. L., Emre, N. C. T., Lamy, L., Ngo, V. N., Wright, G., Xiao, W., Powell, J., Dave, S., Yu, X., Zhao, H., Zeng, Y., Chen, B., Epstein, J., & Staudt, L. M.
- Affiliations
- National Institutes of Health (US)
- University of Arkansas for Medical Sciences (US)
- Corresponding author
- Staudt, Louis M.
- ORCID
- Venue
- Nature
- Published
- 2008-06-22
- Volume
- 454
- Issue
- 7201
- Pages
- 226-231
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2542904
- OpenAlex
- W1981403111
- Cited by
- 730
- References
- 5
- Citations by year
- 2026: 33 · 2025: 40 · 2024: 40 · 2023: 36 · 2022: 44 · 2021: 61 · 2020: 49 · 2019: 39 · 2018: 37 · 2017: 36 · 2016: 39 · 2015: 30 · 2014: 43 · 2013: 51 · 2012: 40
- FWCI
- 24.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (Z99 CA999999)
- National Cancer Institute (R01CA113992, CA 97513, CA113992, R33CA097513)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- IRF4, multiple myeloma, non-oncogene addiction, c-Myc, transcriptional autoregulation, plasma cell differentiation, activated B cells, gene regulatory networks, therapeutic target, RNAi screen, chromatin immunoprecipitation, gene expression profiling
- MeSH terms
- Interferon Regulatory Factor-4, Animals, B-Lymphocytes, Cell Survival, Cell Transformation, Neoplastic, Cells, Cultured, Humans, Multiple Myeloma, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Genes, myc, Proto-Oncogene Proteins c-myc, Gene Expression Profiling, RNA Interference, Chromatin Immunoprecipitation, Interferon Regulatory Factors, Mice
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