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Updated: Feb 4, 2026
Interphase Fluorescence in situ Hybridization of Bone Marrow Smears of Multiple Myeloma
Published on: April 15, 2022
PRC2 targeting is a therapeutic strategy for EZ score defined high-risk multiple myeloma patients and overcome
Laurie Herviou1, Alboukadel Kassambara2,1, Stéphanie Boireau2,1
1IGH, CNRS, Univ Montpellier, Montpellier, France.
Background:
Multiple myeloma (MM) is a malignant plasma cell disease with a poor survival, characterized by the accumulation of myeloma cells (MMCs) within the bone marrow. Epigenetic modifications in MM are associated not only with cancer development and progression, but also with drug resistance.
Methods:
We identified a significant upregulation of the polycomb repressive complex 2 (PRC2) core genes in MM cells in association with proliferation. We used EPZ-6438, a specific small molecule inhibitor of EZH2 methyltransferase activity, to evaluate its effects on MM cells phenotype and gene expression prolile.
Results:
PRC2 targeting results in growth inhibition due to cell cycle arrest and apoptosis together with polycomb, DNA methylation, TP53, and RB1 target genes induction. Resistance to EZH2 inhibitor is mediated by DNA methylation of PRC2 target genes. We also demonstrate a synergistic effect of EPZ-6438 and lenalidomide, a conventional drug used for MM treatment, activating B cell transcription factors and tumor suppressor gene expression in concert with MYC repression. We establish a gene expression-based EZ score allowing to identify poor prognosis patients that could benefit from EZH2 inhibitor treatment.
Conclusions:
These data suggest that PRC2 targeting in association with IMiDs could have a therapeutic interest in MM patients characterized by high EZ score values, reactivating B cell transcription factors, and tumor suppressor genes.
Insights
Targeting polycomb repressive complex 2 (PRC2) with EPZ-6438 inhibits multiple myeloma (MM) cell growth. Combining EPZ-6438 with lenalidomide shows therapeutic promise for MM patients with high EZ scores.
Area of Science:
- Hematology
- Oncology
- Epigenetics
Background:
- Multiple myeloma (MM) is a fatal plasma cell malignancy.
- Epigenetic alterations drive MM progression and drug resistance.
Purpose of the Study:
- Investigate the role of polycomb repressive complex 2 (PRC2) in MM.
- Evaluate the therapeutic potential of EZH2 inhibition in MM.
Main Methods:
- Assessed PRC2 core gene expression in MM cells.
- Utilized EPZ-6438, an EZH2 inhibitor, to study MM cell phenotype and gene expression.
- Investigated synergistic effects of EPZ-6438 with lenalidomide.
Main Results:
- PRC2 targeting induced MM cell cycle arrest, apoptosis, and altered gene expression.
- DNA methylation mediated resistance to EZH2 inhibition.
- EPZ-6438 synergized with lenalidomide, repressing MYC and activating tumor suppressors.
- Developed an EZ score to identify patients benefiting from EZH2 inhibition.
Conclusions:
- PRC2 inhibition combined with immunomodulatory drugs (IMiDs) offers therapeutic potential for MM.
- Targeting EZH2 may benefit MM patients with high EZ scores by reactivating tumor suppressors.
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