Diffuse large B cell lymphoma (DLBCL) is the most diagnosed, aggressive non-Hodgkin lymphoma, with ~40% of patients experiencing refractory or relapsed disease. Given the low response rates to current therapy, alternative treatment strategies are necessary to improve patient outcomes. Here, we sought to develop an easily accessible new xenograft mouse model that better recapitulates the human disease for preclinical studies. We generated two Luciferase (Luc)-EGFP-expressing human DLBCL cell lines representing the different DLBCL cell-of-origin subtypes. After intravenous injection of these cells into humanized NSG mice, we monitored the tumor growth and evaluated the organ-specific engraftment/progression period. Our results showed that human IL6-expressing NSG (NSG-IL6) mice were highly permissive for DLBCL cell growth. In NSG-IL6 mice, systemic engraftments of both U2932 activated B cell-like- and VAL germinal B cell-like-DLBCL (engraftment rate; 75% and 82%, respectively) were detected within 2nd-week post-injection. In the organ-specific ex vivo evaluation, both U2932-Lucand VAL-Luccells were initially engrafted and expanded in the spleen, liver, and lung and subsequently in the skeleton, ovary, and brain. Consistent with the dualBCL2/MYCtranslocation association with poor patient outcomes, VAL cells showed heightened proliferation in human IL6-conditioned media and caused rapid tumor expansion and early death in the engrafted mice. We concluded that the U2932 and VAL cell-derived human IL6-expressing mouse models reproduced the clinical features of an aggressive DLBCL with a highly consistent pattern of tumor development. Based on these findings, NSG mice expressing human IL6 have the potential to serve as a new tool to develop DLBCL xenograft models to overcome the limitations of standard subcutaneous DLBCL xenografts.
弥漫性大B细胞淋巴瘤（DLBCL）是诊断率最高、侵袭性最强的非霍奇金淋巴瘤，约40%的患者会出现难治性或复发性疾病。鉴于当前治疗方案的应答率较低，需要探索替代治疗策略以改善患者预后。本研究旨在开发一种易于构建的新型异种移植小鼠模型，以更好地模拟人类疾病用于临床前研究。我们构建了两种表达荧光素酶（Luc）-EGFP的人源DLBCL细胞系，分别代表不同的DLBCL细胞起源亚型。将这些细胞静脉注射至人源化NSG小鼠体内后，我们监测了肿瘤生长情况并评估了器官特异性植入/进展周期。结果显示，表达人源IL6的NSG（NSG-IL6）小鼠对DLBCL细胞生长具有高度容许性。在NSG-IL6小鼠中，U2932（活化B细胞样）和VAL（生发中心B细胞样）DLBCL细胞系均在注射后第二周内实现系统性植入（植入率分别为75%和82%）。器官特异性离体评估显示，U2932-Luc和VAL-Luc细胞最初在脾脏、肝脏和肺部定植增殖，随后扩散至骨骼、卵巢和脑部。与BCL2/MYC双易位导致患者预后不良的临床特征一致，VAL细胞在人源IL6条件培养基中表现出更强的增殖能力，并在移植小鼠体内引发快速肿瘤扩张和早期死亡。我们得出结论：U2932和VAL细胞构建的人源IL6表达小鼠模型重现了侵袭性DLBCL的临床特征，其肿瘤发展模式具有高度一致性。基于这些发现，表达人源IL6的NSG小鼠有望成为构建DLBCL异种移植模型的新工具，以克服标准皮下DLBCL异种移植模型的局限性。
Development of New Diffuse Large B Cell Lymphoma Mouse Models
肿瘤(癌症)患者之家