Synergistic antitumor effect of combined EZH2 and DOT1L inhibition in B-cell lymphoma Journal Article
| Authors: | Nguyen, V. T. M.; Namba, H.; Porter, H.; Shlyueva, D.; Lopez, E.; Melcher, A.; Béguelin, W.; Melnick, A. M.; Helin, K. |
| Article Title: | Synergistic antitumor effect of combined EZH2 and DOT1L inhibition in B-cell lymphoma |
| Abstract: | Despite the approval of several new treatments for patients with B-cell lymphoma, there is still a large unmet need. Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the 2 most common B-cell lymphoma subtypes, accounting for ∼50% of all cases. EZH2 heterozygous gain-of-function somatic driver mutations are frequently found in germinal center B-cell DLBCLs and FLs. An EZH2 inhibitor has shown durable responses in patients with relapsed or refractory FL, however a considerable fraction of the patients did not show an objective response. To identify alternative therapeutic strategies, we performed CRISPR/Cas9 knockout screens in B-cell lymphoma cells treated with or without an EZH2 inhibitor. This led to the identification of the histone methyltransferase DOT1L as a potential therapeutic target. Specifically, we showed that an EZH2 inhibitor synergizes with a DOT1L inhibitor in a panel of B-cell lymphoma cell lines regardless of the EZH2 mutation status. Mechanistically, we demonstrated that the 2 inhibitors cooperatively suppress DOT1L-regulated cell cycle genes, upregulate genes involved in interferon signaling, including antigen presenting genes, and ultimately drive B-cell differentiation by derepressing EZH2-regulated plasma cell signature genes. Furthermore, we demonstrated the effectiveness of this epigenetic combination strategy in a xenograft model, which led to significant abrogation of tumor growth. Together, our studies provide preclinical proof-of-concept for an epigenetic combination therapy to overcome resistance and improve durability of response for the treatment of B-cell lymphoma, warranting clinical investigation and illustrating an important convergent role of EZH2 and DOT1L in B-cell lymphomagenesis. © 2025 American Society of Hematology |
| Keywords: | controlled study; cancer growth; drug potentiation; nonhuman; antineoplastic agent; mouse; animal tissue; cell cycle; animal experiment; animal model; antineoplastic activity; b cell lymphoma; epigenetics; histone methyltransferase; upregulation; tumor gene; b lymphocyte differentiation; transcription factor ezh2; methyltransferase inhibitor; male; article; crispr-cas9 system |
| Journal Title: | Blood |
| Volume: | 145 |
| Issue: | 24 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2025-01-01 |
| Start Page: | 2873 |
| End Page: | 2886 |
| Language: | English |
| DOI: | 10.1182/blood.2024026534 |
| PUBMED: | 40009485 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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