Britto Lucy S, Balasubramani Deepali, Desai Sona, Phillips Phunterion, Trehan Neev, Cesarman Ethel, Koff Jean L, Singh Ankur
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA.
St Richards Hospital, University Hospitals Sussex NHS Foundation Trust, Chichester, West Sussex, PO19 6SE, UK.
Adv Healthc Mater. 2025 Feb;14(5):e2401192. doi: 10.1002/adhm.202401192. Epub 2024 Jun 28.
Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is a subtype associated with poor survival outcomes. Despite identifying therapeutic targets through molecular characterization, targeted therapies have limited success. New strategies using immune-competent tissue models are needed to understand how DLBCL cells evade treatment. Here, synthetic hydrogel-based lymphoma organoids are used to demonstrate how signals in the lymphoid tumor microenvironment (Ly-TME) can alter B cell receptor (BCR) signaling and specific histone modifications, tri-methylation of histone 3 at lysine 9 (H3K9me3), dampening the effects of BCR pathway inhibition. Using imaging modalities, T cells increase DNA methyltransferase 3A expression and cytoskeleton formation in proximal ABC-DLBCL cells, regulated by H3K9me3. Expansion microscopy on lymphoma organoids reveals T cells increase the size and quantity of segregated H3K9me3 clusters in ABC-DLBCL cells. Findings suggest the re-organization of higher-order chromatin structures that may contribute to evasion or resistance to therapy via the emergence of novel transcriptional states. Treating ABC-DLBCL cells with a G9α histone methyltransferase inhibitor reverses T cell-mediated modulation of H3K9me3 and overcomes T cell-mediated attenuation of treatment response to BCR pathway inhibition. This study emphasizes the Ly-TME's role in altering DLBCL fate and suggests targeting aberrant signaling and microenvironmental cross-talk that can benefit high-risk patients.
活化B细胞样弥漫性大B细胞淋巴瘤（ABC-DLBCL）是一种与生存预后不良相关的亚型。尽管通过分子特征鉴定了治疗靶点，但靶向治疗的成功率有限。需要使用具有免疫活性的组织模型的新策略来了解DLBCL细胞如何逃避治疗。在这里，基于合成水凝胶的淋巴瘤类器官被用于证明淋巴肿瘤微环境（Ly-TME）中的信号如何改变B细胞受体（BCR）信号传导和特定的组蛋白修饰，即组蛋白3赖氨酸9位点的三甲基化（H3K9me3），从而减弱BCR途径抑制的效果。使用成像方式，T细胞增加近端ABC-DLBCL细胞中DNA甲基转移酶3A的表达和细胞骨架形成，这受H3K9me3调控。对淋巴瘤类器官进行扩张显微镜检查发现，T细胞增加了ABC-DLBCL细胞中分离的H3K9me3簇的大小和数量。研究结果表明，高阶染色质结构的重新组织可能通过新转录状态的出现导致逃避治疗或产生耐药性。用G9α组蛋白甲基转移酶抑制剂治疗ABC-DLBCL细胞可逆转T细胞介导的H3K9me3调节，并克服T细胞介导的对BCR途径抑制治疗反应的减弱。这项研究强调了Ly-TME在改变DLBCL命运中的作用，并建议针对异常信号传导和微环境相互作用进行靶向治疗，这可能使高危患者受益。
