ArticleMolecular oncology2018
Dual inhibition of DNMTs and EZH2 can overcome both intrinsic and acquired resistance of myeloma cells to IMiDs in a cereblon-independent manner.
Article in Molecular oncology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 83 citations in OpenAlex.
- Genome-wide DNA methylation analysis pre- and post-lenalidomide treatment in patients with myelodysplastic syndrome with isolated deletion (5q).Annals of hematology · 2021Trial
- Understanding and addressing resistance to IMiDs immunomodulatory compounds in multiple myeloma.The FEBS journal · 2026Review
- EZH2 inhibition overcomes immunomodulatory drug resistance in multiple myeloma via a cereblon-dependent pathway.Haematologica · 2026Article
- Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity.Nature communications · 2026Article
- CRISPR-Cas9 screen reveals that inhibition of enhancer of zeste homolog 2 sensitizes malignant T cells to dimethyl-fumarate-induced cell death.The FEBS journal · 2026Article
- Epigenetic reprogramming in multiple myeloma-Challenges and opportunities.International journal of cancer · 2026Review
- LncSLED1 inhibits monosodium urate-induced macrophage inflammation by promoting Cosmc methylation to upregulate CA72-4.Central-European journal of immunology · 2026Article
- Epigenetic regulation of Cereblon in cancer: molecular mechanisms and clinical implications.Genes & genomics · 2025Article
- Dual EZH1/2 inhibition enhances DNMT inhibitor efficacy in colon cancer through targeting H3K27me1.bioRxiv : the preprint server for biology · 2025Article
- Multiple myeloma associated long non-coding RNA PLUM confers chemoresistance by enhancing PRC2 mediated UPR pathway activation.Nature communications · 2025Article
- Resistance to immunomodulatory drugs in multiple myeloma: the cereblon pathway and beyond.Haematologica · 2025Review
- The Prognostic Potential of circRNAs in Multiple Myeloma: Insights From Whole Bone Marrow and Purified Plasma Cells.Journal of cellular and molecular medicine · 2024Article
- Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation.Journal of hematology & oncology · 2024Article
- Preclinical Evaluation of a Novel Series of Polyfluorinated Thalidomide Analogs in Drug-Resistant Multiple Myeloma.Biomolecules · 2024Article
- Bone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes.Nature communications · 2024Article
- Select EZH2 inhibitors enhance viral mimicry effects of DNMT inhibition through a mechanism involving NFAT:AP-1 signaling.Science advances · 2024Article
- A novel T cell-redirecting anti-GPRC5D × CD3 bispecific antibody with potent antitumor activity in multiple myeloma preclinical models.Scientific reports · 2024Article
- NAT10 MediatesJournal of Cancer · 2024Article
- Unraveling the complexity of drug resistance mechanisms to SINE, T cell-engaging therapies and CELMoDs in multiple myeloma: a comprehensive review.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- Study on the Effect of EZH2 Inhibitor Combined with TIGIT Monoclonal Antibody against Multiple Myeloma Cells.International journal of molecular sciences · 2023Article
5 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism of action. In an effort to comprehend the precise mechanisms behind the development of IMiD resistance and examine whether it is potentially reversible, we established lenalidomide-resistant (-LR) and pomalidomide-resistant (-PR) human myeloma cell lines from two IMiD-sensitive cell lines, OPM2 and NCI-H929, by continuous culture in the presence of lenalidomide or pomalidomide for 4-6 months, until acquirement of stable resistance. By assessing genome-wide DNA methylation and chromatin accessibility in these cell lines, we found that acquired IMiD resistance is associated with an increase in genome-wide DNA methylation and an even greater reduction in chromatin accessibility. Transcriptome analysis confirmed that resistant cell lines are mainly characterized by a reduction in gene expression, identifying SMAD3 as a commonly downregulated gene in IMiD-resistant cell lines. Moreover, we show that these changes are potentially reversible, as combination of 5-azacytidine and EPZ-6438 not only restored the observed accessibility changes and the expression of SMAD3, but also resensitized the resistant cells to both lenalidomide and pomalidomide. Interestingly, the resensitization process was independent of CRBN. Our data suggest that simultaneous inhibition of DNA methyl transferases and EZH2 leads to an extensive epigenetic reprogramming which allows myeloma cells to (re)gain sensitivity to IMiDs.
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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.