Division of Haematological Oncology, Centre for Applied Medical Research (CIMA), CIBERONC, University of Navarra, Pamplona, Spain.
Department of Haematology, University Hospital, and Institute of Molecular and Cellular Biology of Cancer, CIBERONC, University of Salamanca, Salamanca, Spain.
J Pathol. 2018 May;245(1):61-73. doi: 10.1002/path.5060. Epub 2018 Mar 30.
The increased risk of Richter transformation (RT) in patients with chronic lymphocytic leukaemia (CLL) due to Epstein-Barr virus (EBV) reactivation during immunosuppressive therapy with fludarabine other targeted agents remains controversial. Among 31 RT cases classified as diffuse large B-cell lymphoma (DLBCL), seven (23%) showed EBV expression. In contrast to EBV tumours, EBV DLBCLs derived predominantly from IGVH-hypermutated CLL, and they also showed CLL-unrelated IGVH sequences more frequently. Intriguingly, despite having different cellular origins, clonally related and unrelated EBV DLBCLs shared a previous history of immunosuppressive chemo-immunotherapy, a non-germinal centre DLBCL phenotype, EBV latency programme type II or III, and very short survival. These data suggested that EBV reactivation during therapy-related immunosuppression can transform either CLL cells or non-tumoural B lymphocytes into EBV DLBCL. To investigate this hypothesis, xenogeneic transplantation of blood cells from 31 patients with CLL and monoclonal B-cell lymphocytosis (MBL) was performed in Rag2 IL2γc mice. Remarkably, the recipients' impaired immunosurveillance favoured the spontaneous outgrowth of EBV B-cell clones from 95% of CLL and 64% of MBL patients samples, but not from healthy donors. Eventually, these cells generated monoclonal tumours (mostly CLL-unrelated but also CLL-related), recapitulating the principal features of EBV DLBCL in patients. Accordingly, clonally related and unrelated EBV DLBCL xenografts showed indistinguishable cellular, virological and molecular features, and synergistically responded to combined inhibition of EBV replication with ganciclovir and B-cell receptor signalling with ibrutinib in vivo. Our study underscores the risk of RT driven by EBV in CLL patients receiving immunosuppressive therapies, and provides the scientific rationale for testing ganciclovir and ibrutinib in EBV DLBCL. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
由于在接受氟达拉滨和其他靶向药物的免疫抑制治疗期间 EBV 重新激活，慢性淋巴细胞白血病（CLL）患者发生 Richter 转化（RT）的风险增加，这一问题仍存在争议。在 31 例分类为弥漫性大 B 细胞淋巴瘤（DLBCL）的 RT 病例中，有 7 例（23%）显示 EBV 表达。与 EBV 肿瘤不同，源自IGHV 高度突变的 CLL 的 EBV-DLBCL 主要来源于 CLL，并且它们也更频繁地显示出与 CLL 无关的 IGHV 序列。有趣的是，尽管具有不同的细胞起源，但克隆相关和无关的 EBV-DLBCL 具有先前的免疫抑制化疗史、非生发中心 DLBCL 表型、EBV 潜伏程序 II 或 III 以及非常短的存活期。这些数据表明，治疗相关免疫抑制期间 EBV 重新激活可将 CLL 细胞或非肿瘤性 B 淋巴细胞转化为 EBV-DLBCL。为了验证这一假说，对 31 例 CLL 和单克隆 B 细胞淋巴增生症（MBL）患者的血液细胞进行了异种移植实验。令人惊讶的是，受体的免疫监视受损有利于 EBV B 细胞克隆从 95%的 CLL 和 64%的 MBL 患者样本中自发生长，但不能从健康供体中生长。最终，这些细胞产生了单克隆肿瘤（大多数与 CLL 无关，但也有与 CLL 相关的肿瘤），重现了患者体内 EBV-DLBCL 的主要特征。因此，克隆相关和无关的 EBV-DLBCL 异种移植物显示出可区分的细胞、病毒学和分子特征，并且在体内协同响应联合抑制 EBV 复制（更昔洛韦）和 B 细胞受体信号（依鲁替尼）。本研究强调了接受免疫抑制治疗的 CLL 患者发生 EBV 驱动的 RT 的风险，并为测试 EBV-DLBCL 中的更昔洛韦和依鲁替尼提供了科学依据。
