ArticleThe Journal of clinical investigation2015
Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma.
Article in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
What it found
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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.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
63 citing papers in PubMed, 96 citations in OpenAlex.
- Understanding and addressing resistance to IMiDs immunomodulatory compounds in multiple myeloma.The FEBS journal · 2026Review
- Review
- Epigenetic reprogramming in multiple myeloma-Challenges and opportunities.International journal of cancer · 2026Review
- Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)Blood neoplasia · 2025Article
- c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment.Cells · 2025Article
- Review
- The roles of EZH2 in cancer and its inhibitors.Medical oncology (Northwood, London, England) · 2023Review
- EMD originates from hyaluronan-induced homophilic interactions of CD44 variant-expressing MM cells under shear stress.Blood advances · 2023Article
- Expression of integrin β-7 is epigenetically enhanced in multiple myeloma subgroups with high-risk cytogenetics.Clinical epigenetics · 2023Article
- Article
- Role of EZH2 in Uterine Gland Development.International journal of molecular sciences · 2022Article
- CAF-derived midkine promotes EMT and cisplatin resistance by upregulating lncRNA ST7-AS1 in gastric cancer.Molecular and cellular biochemistry · 2022Article
- Epigenetic Crosstalk between Malignant Plasma Cells and the Tumour Microenvironment in Multiple Myeloma.Cancers · 2022Review
- Review
- SORT1/LAMP2-mediated extracellular vesicle secretion and cell adhesion are linked to lenalidomide resistance in multiple myeloma.Blood advances · 2022Article
- Article
- Mechanisms of Polycomb group protein function in cancer.Cell research · 2022Review
- Article
- Connections between metabolism and epigenetics: mechanisms and novel anti-cancer strategy.Frontiers in pharmacology · 2022Review
- Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer.Journal of experimental & clinical cancer research : CR · 2021Review
3 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Alterations in chromatin modifications, such as histone methylation, have been suggested as mediating chemotherapy resistance in several cancer types; therefore, elucidation of the epigenetic mechanisms that underlie drug resistance may greatly contribute to the advancement of cancer therapies. In the present study, we identified histone H3-lysine 27 (H3K27) as a critical residue for epigenetic modification in multiple myeloma. We determined that abrogation of drug-induced H3K27 hypermethylation is associated with cell adhesion-mediated drug resistance (CAM-DR), which is the most important form of drug resistance, using a coculture system to evaluate stroma cell adhesion-dependent alterations in multiple myeloma cells. Cell adhesion counteracted anticancer drug-induced hypermethylation of H3K27 via inactivating phosphorylation of the transcription regulator EZH2 at serine 21, leading to the sustained expression of antiapoptotic genes, including IGF1, B cell CLL/lymphoma 2 (BCL2), and hypoxia inducible factor 1, α subunit (HIF1A). Pharmacological and genetic inhibition of the IGF-1R/PI3K/AKT pathway reversed CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation both in vitro and in refractory murine myeloma models. Together, our findings identify and characterize an epigenetic mechanism that underlies CAM-DR and suggest that kinase inhibitors to counteract EZH2 phosphorylation should be included in combination chemotherapy to increase therapeutic index.
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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.