Vakiani Efsevia, Basso Katia, Klein Ulf, Mansukhani Mahesh M, Narayan Gopeshwar, Smith Paula M, Murty Vundavalli V, Dalla-Favera Riccardo, Pasqualucci Laura, Bhagat Govind
Department of Pathology, Columbia University, New York, NY 10032, USA.
Hematol Oncol. 2008 Dec;26(4):199-211. doi: 10.1002/hon.859.
B-cell post-transplant lymphoproliferative disorders (PTLD) are classified as early lesions, polymorphic lymphomas (P-PTLD) and monomorphic lymphomas (M-PTLD). These morphologic categories are thought to reflect a biologic continuum, although supporting genetic data are lacking. To gain better insights into PTLD pathogenesis, we characterized the phenotypes, immunoglobulin (Ig) gene alterations and non-Ig gene (BCL6, RhoH/TTF, c-MYC, PAX5, CIITA, BCL7A, PIM1) mutations of 21 PTLD, including an IM-like lesion, 8 P-PTLD and 12 M-PTLD. Gene expression profile analysis was also performed in 12 cases. All PTLD with clonal Ig rearrangements showed evidence of germinal centre (GC) transit based on the analysis of Ig and BCL6 gene mutations, and 74% had a non-GC phenotype (BCL6 +/- MUM1+). Although surface Ig abnormalities were seen in 6/19 (32%) PTLD, only three showed 'crippling' Ig mutations indicating other etiologies for loss of the B-cell receptor. Aberrant somatic hypermutation (ASHM) was almost exclusively observed in M-PTLD (8/12 vs. 1/8 P-PTLD) and all three recurrent cases analysed showed additional mutations in genes targeted by ASHM. Gene expression analysis showed distinct clustering of PTLD compared to B-cell non-Hodgkin lymphomas (B-NHL) without segregation of P-PTLD from non-GC M-PTLD or EBV+ from EBV- PTLD. The gene expression pattern of PTLD appeared more related to that of memory and activated B-cells. Together, our results suggest that PTLD represent a distinct type of B-NHL deriving from an antigen experienced B-cell, whose evolution is associated with accrual of genetic lesions.
B细胞移植后淋巴组织增生性疾病（PTLD）分为早期病变、多形性淋巴瘤（P-PTLD）和单形性淋巴瘤（M-PTLD）。尽管缺乏支持性的遗传学数据，但这些形态学分类被认为反映了一个生物学连续谱。为了更好地了解PTLD的发病机制，我们对21例PTLD的表型、免疫球蛋白（Ig）基因改变和非Ig基因（BCL6、RhoH/TTF、c-MYC、PAX5、CIITA、BCL7A、PIM1）突变进行了特征分析，其中包括1例IM样病变、8例P-PTLD和12例M-PTLD。还对12例病例进行了基因表达谱分析。基于Ig和BCL6基因突变分析，所有具有克隆性Ig重排的PTLD均显示有生发中心（GC）转移的证据，且74%具有非GC表型（BCL6+/-MUM1+）。尽管在19例（32%）PTLD中观察到表面Ig异常，但只有3例显示“致残性”Ig突变，提示B细胞受体缺失的其他病因。异常体细胞超突变（ASHM）几乎仅在M-PTLD中观察到（12例中有8例，而P-PTLD中有8例中的1例），并且分析的所有3例复发病例均显示在ASHM靶向的基因中有额外突变。基因表达分析显示，与B细胞非霍奇金淋巴瘤（B-NHL）相比，PTLD有明显的聚类，P-PTLD与非GC M-PTLD或EBV+与EBV-PTLD之间没有分离。PTLD的基因表达模式似乎与记忆性和活化B细胞的模式更相关。总之，我们的结果表明，PTLD代表一种源自经历过抗原刺激的B细胞的独特类型的B-NHL，其演变与遗传损伤的积累有关。
