Capello Daniela, Cerri Michaela, Muti Giuliana, Berra Eva, Oreste Pierluigi, Deambrogi Clara, Rossi Davide, Dotti Giampietro, Conconi Annarita, Viganò Mario, Magrini Umberto, Ippoliti Giovanbattista, Morra Enrica, Gloghini Annunziata, Rambaldi Alessandro, Paulli Marco, Carbone Antonino, Gaidano Gianluca
Hematology Unit, Department of Medical Sciences & Interdisciplinary Research Center on Autoimmune Diseases, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy.
Blood. 2003 Nov 15;102(10):3775-85. doi: 10.1182/blood-2003-05-1683. Epub 2003 Aug 7.
Posttransplantation lymphoproliferative disorders (PTLDs) represent a serious complication of solid organ transplantation. This study assessed the molecular histogenesis of 52 B-cell monoclonal PTLDs, including 12 polymorphic PTLDs (P-PTLDs), 36 diffuse large B-cell lymphomas (DLBCLs), and 4 Burkitt/Burkitt-like lymphomas (BL/BLLs). Somatic hypermutation (SHM) of immunoglobulin variable (IgV) genes documented that most monoclonal B-cell PTLDs (75% P-PTLDs, 91.3% DLBCLs, 100% BL/BLLs) derive from germinal center (GC)-experienced B cells. B-cell lymphoma 6 (BCL6) mutations occurred in 25% P-PTLDs, 60.6% DLBCLs, and 75.0% BL/BLLs. A first histogenetic category of PTLDs (31.2% DLBCLs) express the BCL6+/multiple myeloma oncogene-1 protein (MUM1-/+)/CD138- profile and mimic B cells experiencing the GC reaction, as also suggested by ongoing SHM in a fraction of these cases. A second subset of PTLDs (66.7% P-PTLDs and 31.2% DLBCLs) display the BCL6-/MUM1+/CD138- phenotype and mimic B cells that have concluded the GC reaction. A third histogenetic category of PTLDs (25.0% P-PTLDs and 31.2% DLBCLs) shows the BCL6-/MUM1+/CD138+ profile, consistent with preterminally differentiated post-GC B cells. Crippling mutations of IgV heavy chain (IgVH) and/or IgV light chain (IgVL) genes, leading to sterile rearrangements and normally preventing cell survival, occur in 4 DLBCLs and 1 BL/BLL that may have been rescued from apoptosis through expression of Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1). Overall, the histogenetic diversity of monoclonal B-cell PTLDs may help define biologically homogeneous categories of the disease.
移植后淋巴细胞增生性疾病（PTLD）是实体器官移植的一种严重并发症。本研究评估了52例B细胞单克隆PTLD的分子组织发生情况，包括12例多形性PTLD（P-PTLD）、36例弥漫性大B细胞淋巴瘤（DLBCL）和4例伯基特/伯基特样淋巴瘤（BL/BLL）。免疫球蛋白可变区（IgV）基因的体细胞超突变（SHM）表明，大多数单克隆B细胞PTLD（75%的P-PTLD、91.3%的DLBCL、100%的BL/BLL）来源于经历生发中心（GC）的B细胞。B细胞淋巴瘤6（BCL6）突变发生在25%的P-PTLD、60.6%的DLBCL和75.0%的BL/BLL中。PTLD的第一类组织发生类型（31.2%的DLBCL）表达BCL6+/多发性骨髓瘤癌基因1蛋白（MUM1-/+）/CD138-表型，模拟经历GC反应的B细胞，部分病例中持续存在的SHM也提示了这一点。PTLD的第二个亚组（66.7%的P-PTLD和31.2%的DLBCL）表现出BCL6-/MUM1+/CD138-表型，模拟已完成GC反应的B细胞。PTLD的第三类组织发生类型（25.0%的P-PTLD和31.2%的DLBCL）显示BCL6-/MUM1+/CD138+表型，与GC后终末前分化的B细胞一致。IgV重链（IgVH）和/或IgV轻链（IgVL）基因的严重突变导致无效重排并通常阻止细胞存活，在4例DLBCL和1例BL/BLL中出现，这些病例可能通过表达爱泼斯坦-巴尔病毒（EBV）编码的潜伏膜蛋白1（LMP1）从凋亡中获救。总体而言，单克隆B细胞PTLD的组织发生多样性可能有助于定义该疾病的生物学同质性类别。
