霍奇金淋巴瘤亚型Richter综合征免疫球蛋白重链可变区基因突变及克隆相关性分析  

Clonality analysis and mutational status of lgVH gene in Hodgkin variant of Richter syndrome

作　　者：毛峥嵘[1] Andreas Rosenwald 章锁江[1] 周韧[1] Hans Konrad Mueller-Hermelink 

机构地区：[1]浙江大学医学院病理与病理生理学系,杭州310058 [2]Pathology Institute, Wuerzburg University, Germany

出　　处：《中华病理学杂志》2008年第8期523-528,共6页Chinese Journal of Pathology

基　　金：国家自然科学基金资助项目（30770918）;国家留学基金委员会及德国Hanns-Seidel Stiftung基金资助项目（20033008）;浙江省自然科学基金资助项目（Y205292）;浙江省人事厅留学人员科技活动择优资助项目（2007-324）

摘　　要：目的检测霍奇金淋巴瘤（HL）亚型Richter综合征免疫球蛋白重链可变区（IgVH）基因重排、突变、克隆相关性等基因特征及其与预后的关系，初步探讨其可能涉及的分子机制。方法用基因扫描分析HL亚型Richter综合征及慢性B淋巴细胞性白血病（B—CLL）伴CD30阳性R—S细胞样细胞病例IgVH基因的克隆性重排，测序分析IgVH基因的突变状态及其分子特征；用激光显微切割结合半套式PCR扩增R—S细胞和R—S细胞样细胞的IgVH基因，比较两种肿瘤成分的克隆相关性；用免疫组织化学LAB—SA法检测两种肿瘤中zeta相关蛋白70（ZAP70）、p53、干扰素调节因子4（IRF-4）及EB病毒潜伏膜蛋白-1（LMP1）等因子表达的不同。结果（1）6例向HL转化及6例向R—S细胞样细胞转化的B—CLL患者中，携带突变型IgVH基因的患者各占5例；（2）4例IgVH基因克隆相关性分析中，与相应B—CLL克隆不相关的2例R-S细胞和1例R—S细胞样细胞表达LMP1。而1例与B—CLL来自相同克隆的R—S细胞样细胞不表达LMP1；（3）HL亚型Richter综合征中B—CLL肿瘤细胞常使用的IgVH基因是VH3和VH4家族，6例中各有2例使用VH4—34和VH3-48基因。结论（1）转化的HL和R—S细胞样细胞主要与生发中心或生发中心后的B—CLL有关，提示不同类型的Richter综合征可能涉及的发病机制不同；（2）HL与R—S细胞样细胞既可以是B—CLL克隆相关病例，也可以是克隆不相关的病例。而后者可能与B—CLL患者免疫抑制后继发EB病毒感染有关；（3）IgVH基因在HL亚型Richter综合征B—CLL中的偏向性使用，提示抗原在转化中的作用。Objective To detect the clonal relationship, the rearrangement, and the mutational status of IgVH gene; the influence of these molecular characteristics on the clinical outcome in Hodgkin variant of Richter syndrome; and the possible molecular pathogenesis in this transformation. Methods The clonal rearrangements and mutational status of IgVH genes were analyzed in Hodgkin variant of Richter syndrome and B-CLL with Reed-Steinberg （R-S） -like cells by GeneScan analysis and sequencing. Semi-nest PCR based on laser capture microdissection was utilized to compare the clonal relationship between B-CLL and R-S/R-Slike cells. Immunohistochemical staining was used to detect the different expressions of ZAP70, p53, IRF-4 and LMP1 in the two components. Results （ 1 ） 5/6 B-CLL cases transformed to Hodgkin lymphoma （HL）/R-S-like cells carried the mutated IgVH genes; （2） 2 cases of R-S cells and 1 case of R-S-like cells were clonally distinct from B-CLL clone and express LMP1, whereas 1 case of R-S-like cells was relating to the surrounding B-CLL cells and did not express LMP1 ; （3） 2/6 B-CLL cases transformed to HLconvey VH4-34 and VH3-48respectively. Conclusions （ 1 ） Richtertransformation to HL/R-S-like cells evolves from the B-CLL which originates from the germinal center or post germinal center B cells, indicating that different lymphoma cells of different subtypes in Richter syndrome come from different B cell lineage and possibly involve a different pathogenesis and pathway; （2） HL and R-S-like cells evolve from either the B-CLL clone or may develop as a clonally unrelated lymphoma, the independent secondary malignancies are appear to be EBV-positive, possibly as a consequence of the underlying immunodeficiency; （3） The biased usage of IgVH genes suggested a role of antigens involved in the HL variant of Richter syndrome.

关 键 词：淋巴瘤 白血病 粒细胞 慢性 突变 免疫表型分型 基因重排 B淋巴细胞 重链 

分 类 号：R686[医药卫生—骨科学]