Targeting DOT1L and EZH2 synergizes in breaking the germinal center identity of diffuse large B-cell lymphoma
Differentiation of antigen-activated B cells into proproliferative germinal center (GC) B cells depends on the activity of the transcription factors myelocytoma (MYC) and B-cell lymphoma 6 (BCL6), and the epigenetic writers disruptor of telomeric silencing 1-like (DOT1L) and enhancer of zeste homolo...
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| Vydané v: | Blood Ročník 145; číslo 16; s. 1802 |
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| Hlavní autori: | , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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United States
17.04.2025
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| ISSN: | 1528-0020, 1528-0020 |
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| Abstract | Differentiation of antigen-activated B cells into proproliferative germinal center (GC) B cells depends on the activity of the transcription factors myelocytoma (MYC) and B-cell lymphoma 6 (BCL6), and the epigenetic writers disruptor of telomeric silencing 1-like (DOT1L) and enhancer of zeste homolog 2 (EZH2). GCB-like diffuse large B-cell lymphomas (GCB-DLBCLs) arise from GCB cells and closely resemble their cell of origin. Given the dependency of GCB cells on DOT1L and EZH2, we investigated the role of these epigenetic regulators in GCB-DLBCLs and observed that GCB-DLBCLs synergistically depend on the combined activity of DOT1L and EZH2. Mechanistically, inhibiting both enzymes led to enhanced derepression of polycomb repressive complex 2 target genes compared with EZH2 single treatment, along with the upregulation of BCL6 target genes and suppression of MYC target genes. The sum of all these alterations results in a "cell identity crisis," wherein GCB-DLBCLs lose their proproliferative GC identity and partially undergo plasma cell differentiation, a state associated with poor survival. In support of this model, combined epidrugging of DOT1L and EZH2 prohibited the outgrowth of human GCB-DLBCL xenografts in vivo. We conclude that the malignant behavior of GCB-DLBCLs strongly depends on DOT1L and EZH2 and that combined targeting of both epigenetic writers may provide an alternative differentiation-based treatment modality for GCB-DLBCL. |
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| AbstractList | Differentiation of antigen-activated B cells into pro-proliferative germinal center (GC) B cells depends on the activity of the transcription factors MYC and BCL6, and the epigenetic writers DOT1L and EZH2. GCB-like Diffuse Large B Cell Lymphomas (GCB-DLBCLs) arise from GCB cells and closely resemble their cell of origin. Given the dependency of GCB cells on DOT1L and EZH2, we investigated the role of these epigenetic regulators in GCB-DLBCLs and observed that GCB-DLBCLs synergistically depend on the combined activity of DOT1L and EZH2. Mechanistically, inhibiting both enzymes led to enhanced derepression of PRC2 target genes compared to EZH2 single treatment, along with the upregulation of BCL6 target genes and suppression of MYC target genes. The sum of all these alterations results in a 'cell identity crisis', wherein GCB-DLBCLs lose their pro-proliferative GC identity and partially undergo PC differentiation, a state associated with poor survival. In support of this model, combined epi-drugging of DOT1L and EZH2 prohibited the outgrowth of human GCB-DLBCL xenografts in vivo. We conclude that the malignant behavior of GCB-DLBCLs strongly depends on DOT1L and EZH2 and that combined targeting of both epigenetic writers may provide an alternative differentiation-based treatment modality for GCB-DLBCL.Differentiation of antigen-activated B cells into pro-proliferative germinal center (GC) B cells depends on the activity of the transcription factors MYC and BCL6, and the epigenetic writers DOT1L and EZH2. GCB-like Diffuse Large B Cell Lymphomas (GCB-DLBCLs) arise from GCB cells and closely resemble their cell of origin. Given the dependency of GCB cells on DOT1L and EZH2, we investigated the role of these epigenetic regulators in GCB-DLBCLs and observed that GCB-DLBCLs synergistically depend on the combined activity of DOT1L and EZH2. Mechanistically, inhibiting both enzymes led to enhanced derepression of PRC2 target genes compared to EZH2 single treatment, along with the upregulation of BCL6 target genes and suppression of MYC target genes. The sum of all these alterations results in a 'cell identity crisis', wherein GCB-DLBCLs lose their pro-proliferative GC identity and partially undergo PC differentiation, a state associated with poor survival. In support of this model, combined epi-drugging of DOT1L and EZH2 prohibited the outgrowth of human GCB-DLBCL xenografts in vivo. We conclude that the malignant behavior of GCB-DLBCLs strongly depends on DOT1L and EZH2 and that combined targeting of both epigenetic writers may provide an alternative differentiation-based treatment modality for GCB-DLBCL. Differentiation of antigen-activated B cells into proproliferative germinal center (GC) B cells depends on the activity of the transcription factors myelocytoma (MYC) and B-cell lymphoma 6 (BCL6), and the epigenetic writers disruptor of telomeric silencing 1-like (DOT1L) and enhancer of zeste homolog 2 (EZH2). GCB-like diffuse large B-cell lymphomas (GCB-DLBCLs) arise from GCB cells and closely resemble their cell of origin. Given the dependency of GCB cells on DOT1L and EZH2, we investigated the role of these epigenetic regulators in GCB-DLBCLs and observed that GCB-DLBCLs synergistically depend on the combined activity of DOT1L and EZH2. Mechanistically, inhibiting both enzymes led to enhanced derepression of polycomb repressive complex 2 target genes compared with EZH2 single treatment, along with the upregulation of BCL6 target genes and suppression of MYC target genes. The sum of all these alterations results in a "cell identity crisis," wherein GCB-DLBCLs lose their proproliferative GC identity and partially undergo plasma cell differentiation, a state associated with poor survival. In support of this model, combined epidrugging of DOT1L and EZH2 prohibited the outgrowth of human GCB-DLBCL xenografts in vivo. We conclude that the malignant behavior of GCB-DLBCLs strongly depends on DOT1L and EZH2 and that combined targeting of both epigenetic writers may provide an alternative differentiation-based treatment modality for GCB-DLBCL. |
| Author | Traets, Joleen Bleijerveld, Onno B Kersten, Marie José Morris, Ben Jayachandran, Jayashree Göbel, Camiel de Groot, Marnix H P Kloosterman, Daan J Aslam, Muhammad A Oskam, Nienke Kreft, Maaike Jacobs, Heinz Song, Ji-Ying de Groot, Daniel Azarang, Leyla Niccolai, Rachele Hoekman, Liesbeth Gregoricchio, Sebastian Kasa, Eirini van Leeuwen, Fred |
| Author_xml | – sequence: 1 givenname: Camiel surname: Göbel fullname: Göbel, Camiel organization: Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 2 givenname: Rachele surname: Niccolai fullname: Niccolai, Rachele organization: Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 3 givenname: Marnix H P surname: de Groot fullname: de Groot, Marnix H P organization: Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 4 givenname: Jayashree surname: Jayachandran fullname: Jayachandran, Jayashree organization: Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 5 givenname: Joleen surname: Traets fullname: Traets, Joleen organization: Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 6 givenname: Daan J orcidid: 0000-0003-1082-070X surname: Kloosterman fullname: Kloosterman, Daan J organization: Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 7 givenname: Sebastian orcidid: 0000-0001-9209-5403 surname: Gregoricchio fullname: Gregoricchio, Sebastian organization: Department of Oncogenomics, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 8 givenname: Ben surname: Morris fullname: Morris, Ben organization: Robotics and Screening Center, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 9 givenname: Maaike orcidid: 0000-0003-1301-2898 surname: Kreft fullname: Kreft, Maaike organization: Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 10 givenname: Ji-Ying surname: Song fullname: Song, Ji-Ying organization: Division of Experimental Animal Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 11 givenname: Leyla orcidid: 0000-0001-5163-081X surname: Azarang fullname: Azarang, Leyla organization: Biostatistics Center, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 12 givenname: Eirini surname: Kasa fullname: Kasa, Eirini organization: Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 13 givenname: Nienke surname: Oskam fullname: Oskam, Nienke organization: Immunopathology, Sanquin Research, Amsterdam, The Netherlands – sequence: 14 givenname: Daniel surname: de Groot fullname: de Groot, Daniel organization: Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 15 givenname: Liesbeth orcidid: 0000-0002-3552-6390 surname: Hoekman fullname: Hoekman, Liesbeth organization: Mass Spectrometry/Proteomics Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 16 givenname: Onno B surname: Bleijerveld fullname: Bleijerveld, Onno B organization: Mass Spectrometry/Proteomics Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 17 givenname: Marie José surname: Kersten fullname: Kersten, Marie José organization: Department of Hematology, Amsterdam University Medical Center (location University of Amsterdam), Cancer Center Amsterdam, Amsterdam, The Netherlands – sequence: 18 givenname: Muhammad A orcidid: 0000-0003-1905-2583 surname: Aslam fullname: Aslam, Muhammad A organization: Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan – sequence: 19 givenname: Fred orcidid: 0000-0002-7267-7251 surname: van Leeuwen fullname: van Leeuwen, Fred organization: Department of Medical Biology, Amsterdam University Medical Center (location University of Amsterdam), Amsterdam, The Netherlands – sequence: 20 givenname: Heinz orcidid: 0000-0001-6227-9850 surname: Jacobs fullname: Jacobs, Heinz organization: Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands |
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| Copyright | 2025 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies. Copyright © 2025 American Society of Hematology. |
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| References | 40244641 - Blood. 2025 Apr 17;145(16):1714-1715. doi: 10.1182/blood.2024027324. |
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| Snippet | Differentiation of antigen-activated B cells into proproliferative germinal center (GC) B cells depends on the activity of the transcription factors... Differentiation of antigen-activated B cells into pro-proliferative germinal center (GC) B cells depends on the activity of the transcription factors MYC and... |
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| SubjectTerms | Animals Cell Differentiation Cell Line, Tumor Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors Enhancer of Zeste Homolog 2 Protein - genetics Enhancer of Zeste Homolog 2 Protein - metabolism Epigenesis, Genetic Gene Expression Regulation, Neoplastic - drug effects Germinal Center - drug effects Germinal Center - metabolism Germinal Center - pathology Histone-Lysine N-Methyltransferase - antagonists & inhibitors Humans Lymphoma, Large B-Cell, Diffuse - drug therapy Lymphoma, Large B-Cell, Diffuse - genetics Lymphoma, Large B-Cell, Diffuse - metabolism Lymphoma, Large B-Cell, Diffuse - pathology Mice |
| Title | Targeting DOT1L and EZH2 synergizes in breaking the germinal center identity of diffuse large B-cell lymphoma |
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