ArticleBlood cancer discovery2024
Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma.
Article in Blood cancer discovery, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
37 citing papers in PubMed, 34 citations in OpenAlex.
- A positive feedback loop between YTHDC1 and EP300 drives multiple myeloma tumorigenesis.Oncogene · 2026Article
- Integrated Genomic and Epigenomic Analysis Reveals Epigenetic Plasticity in Disease Progression and Multidrug Resistance in Multiple Myeloma.Cancer research · 2026Article
- Understanding and addressing resistance to IMiDs immunomodulatory compounds in multiple myeloma.The FEBS journal · 2026Review
- Drug Resistance in Multiple Myeloma: Tumor-Intrinsic Mechanisms and the Bone Marrow Microenvironment.Cell biochemistry and function · 2026Review
- EZH2 inhibition overcomes immunomodulatory drug resistance in multiple myeloma via a cereblon-dependent pathway.Haematologica · 2026Article
- Article
- Decoding immunotherapy resistance in multiple myeloma: genetic insights and approaches to counter resistance.Science China. Life sciences · 2026Review
- Multiple myeloma: A tale of deregulated transcription factors.HemaSphere · 2026Review
- An orally active dual CBP/p300 degrader targets core dependencies of multiple myeloma.Cell reports · 2026Article
- 3D chromatin architecture in cancer: mechanisms of dysregulation and emerging therapeutic strategies.Experimental & molecular medicine · 2026Review
- Targeting PRKCN, an Essential Driver Orchestrating mTOR-IRF4 Axis Independently of Kinase Activity, in Multiple Myeloma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Chromatin Accessibility in Cancer: Biological Functions, Mechanisms, Therapeutic Potential, and Future Directions.MedComm · 2026Review
- Bioenergetic diversity and nutrient auxotrophy shape the metabolic landscape of multiple myeloma.Blood advances · 2026Article
- Catalytic Inhibition of p300 Preferentially Targets IRF4 Oncogenic Activity and Tumor Growth in Multiple Myeloma.Cancer research · 2026Article
- Article
- Epigenetic reprogramming in multiple myeloma-Challenges and opportunities.International journal of cancer · 2026Review
- Decoding cancer heterogeneity through super-enhancer landscapes: from subtype discovery to therapeutic opportunity.Briefings in bioinformatics · 2025Review
- Systemic deficits in lipid homeostasis promote aging-associated impairments in B cell progenitor development.GeroScience · 2025Article
- GCK inhibition enhances iberdomide antimyeloma effects by promoting IKZF1 degradation via a CRBN-independent mechanism.Blood neoplasia · 2025Article
- A novel cereblon variant with both exon 8 and 10 deletions in newly diagnosed and relapsed multiple myeloma.Blood neoplasia · 2025Article
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Authors and funding
33 authors at 6 institutions in 2 countries.
Funding
Abstract
Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiD). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance. SIGNIFICANCE: These results highlight the dependence of MM on IKZF1-bound super-enhancers, which can be effectively targeted by a potent therapeutic combination pairing IMiD-mediated degradation of IKZF1 and IKZF3 with EP300 inhibition. They also identify AP-1 factors as an unrecognized mechanism of IMiD resistance in MM. See related article by Neri, Barwick, et al., p. 56. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.