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Updated: Dec 3, 2025
VDJ-Seq: Deep Sequencing Analysis of Rearranged Immunoglobulin Heavy Chain Gene to Reveal Clonal Evolution Patterns of B Cell Lymphoma
Published on: December 28, 2015
Combined EZH2 and Bcl-2 inhibitors as precision therapy for genetically defined DLBCL subtypes
Hanna Scholze1, Regan E Stephenson2, Raymond Reynolds3
1Department of Pediatrics, Weill Cornell Medical College, New York, NY.
Abstract:
Molecular alterations in the histone methyltransferase EZH2 and the antiapoptotic protein Bcl-2 frequently co-occur in diffuse large B-cell lymphoma (DLBCL). Because DLBCL tumors with these characteristics are likely dependent on both oncogenes, dual targeting of EZH2 and Bcl-2 is a rational therapeutic approach. We hypothesized that EZH2 and Bcl-2 inhibition would be synergistic in DLBCL. To test this, we evaluated the EZH2 inhibitor tazemetostat and the Bcl-2 inhibitor venetoclax in DLBCL cells, 3-dimensional lymphoma organoids, and patient-derived xenografts (PDXs). We found that tazemetostat and venetoclax are synergistic in DLBCL cells and 3-dimensional lymphoma organoids that harbor an EZH2 mutation and an IGH/BCL2 translocation but not in wild-type cells. Tazemetostat treatment results in upregulation of proapoptotic Bcl-2 family members and priming of mitochondria to BH3-mediated apoptosis, which may sensitize cells to venetoclax. The combination of tazemetostat and venetoclax was also synergistic in vivo. In DLBCL PDXs, short-course combination therapy resulted in complete remissions that were durable over time and associated with superior overall survival compared with either drug alone.
Insights
Dual targeting of EZH2 and Bcl-2 with tazemetostat and venetoclax showed synergistic effects in diffuse large B-cell lymphoma (DLBCL). This combination achieved durable complete remissions and improved survival in patient-derived xenografts.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Diffuse large B-cell lymphoma (DLBCL) often exhibits co-occurring molecular alterations in EZH2 and Bcl-2.
- These alterations suggest a potential oncogene addiction, making dual targeting a rational therapeutic strategy.
Purpose of the Study:
- To investigate the synergistic potential of combining EZH2 inhibition (tazemetostat) with Bcl-2 inhibition (venetoclax) in DLBCL.
Main Methods:
- Evaluation of tazemetostat and venetoclax in DLBCL cell lines, 3D lymphoma organoids, and patient-derived xenografts (PDXs).
- Assessment of drug synergy, molecular changes, and in vivo efficacy.
Main Results:
- Tazemetostat and venetoclax demonstrated synergistic effects in DLBCL cells and organoids with specific EZH2 mutations and IGH/BCL2 translocations.
- Tazemetostat upregulated proapoptotic proteins, sensitizing cells to venetoclax.
- Combination therapy achieved synergistic effects in vivo, leading to durable complete remissions and superior overall survival in DLBCL PDXs.
Conclusions:
- Dual inhibition of EZH2 and Bcl-2 is a promising synergistic therapeutic strategy for specific subtypes of DLBCL.
- Combination therapy with tazemetostat and venetoclax offers a potent approach for treating DLBCL, showing significant efficacy in preclinical models.
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