Göbel Camiel, Niccolai Rachele, de Groot Marnix H P, Jayachandran Jayashree, Traets Joleen, Kloosterman Daan J, Gregoricchio Sebastian, Morris Ben, Kreft Maaike, Song Ji-Ying, Azarang Leyla, Kasa Eirini, Oskam Nienke, de Groot Daniel, Hoekman Liesbeth, Bleijerveld Onno B, Kersten Marie José, Aslam Muhammad A, van Leeuwen Fred, Jacobs Heinz
Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Oncogenomics, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Blood. 2025 Apr 17;145(16):1802-1813. doi: 10.1182/blood.2024025500.
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.
抗原激活的B细胞分化为促增殖生发中心（GC）B细胞取决于转录因子髓细胞瘤（MYC）和B细胞淋巴瘤6（BCL6）的活性，以及表观遗传书写因子端粒沉默破坏因子1样蛋白（DOT1L）和zeste同源物2增强子（EZH2）。GCB样弥漫性大B细胞淋巴瘤（GCB-DLBCL）起源于GCB细胞，与它们的起源细胞极为相似。鉴于GCB细胞对DOT1L和EZH2的依赖性，我们研究了这些表观遗传调节因子在GCB-DLBCL中的作用，并观察到GCB-DLBCL协同依赖于DOT1L和EZH2的联合活性。从机制上讲，与单独抑制EZH2相比，同时抑制这两种酶导致多梳抑制复合物2靶基因的去抑制增强，同时BCL6靶基因上调，MYC靶基因受到抑制。所有这些改变的总和导致了一种“细胞身份危机”，其中GCB-DLBCL失去了其促增殖的GC身份，并部分经历浆细胞分化，这种状态与较差的生存率相关。支持这一模型的是，联合表观遗传药物抑制DOT1L和EZH2可在体内阻止人GCB-DLBCL异种移植瘤的生长。我们得出结论，GCB-DLBCL的恶性行为强烈依赖于DOT1L和EZH2，同时靶向这两种表观遗传书写因子可能为GCB-DLBCL提供一种基于分化的替代治疗方式。
