Tobin Gerard
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Ups J Med Sci. 2005;110(2):97-113. doi: 10.3109/2000-1967-075.
The somatic hypermutation (SMH) status of the immunoglobulin (Ig) V(H) genes can divide chronic lymphocytic leukemia (CLL) into two prognostic subsets, with mutated V(H) genes display superior survival compared to unmutated cases. Biased V(H) gene usage has also been reported in CLL which may reflect antigen selection. In a V(H) gene analysis of 265 CLL cases we confirmed the prognostic impact of the V(H) mutation status and found preferential V(H) gene usage in both the mutated and unmutated subset. Interestingly, CLL cases rearranging one particular V(H) gene, V(H)3-21, displayed poor outcome despite that two-thirds showed mutated V(H) genes. Many of the V(H)3-21 utilizing cases expressed lambda light chains, rearranged a Vlambda2-14 gene, and had homologous complementarity determining region 3s (CDR3s), implying recognition of a common antigen epitope. We thus believe that the cases rearranging the V(H)3-21 gene comprises an additional CLL entity. We further analyzed the V(H) gene rearrangements and, specifically, the heavy chain CDR3 sequences in 346 CLL cases to investigate the role of antigens in CLL. We identified six new subgroups with similar HCDR3 features and restricted VL gene usage as in the V(H)3-21-using group. Our data indicate a limited number of antigen recognition sites in these subgroups and give further evidence for antigen selection in the development of CLL. Different mutational cutoffs have been used to distinguish mutated CLL in addition to the 2% cutoff. Using three levels of somatic mutations we divided 323 CLLs into subsets with divergent survival (<2%, 2-5% and >5% mutations). This division revealed a low-mutated subgroup (2-5%) with inferior outcome that would have been masked using the traditional 2% cutoff. A 1513A/C polymorphism in the P2X(7) receptor gene was reported to be more frequent in CLL, but no difference in genotype frequencies was revealed in our 170 CLL cases and 200 controls. However, CLL cases with the 1513AC genotype showed superior survival than 1513AA cases and this was in particular confined to CLL with mutated VH genes. In summary, we could define new prognostic subgroups in CLL using Ig gene rearrangement analysis. This also allowed us to gain insights in the biology and potential role of antigen involvement in the pathogenesis of CLL.
免疫球蛋白（Ig）V(H)基因的体细胞高频突变（SMH）状态可将慢性淋巴细胞白血病（CLL）分为两个预后亚组，V(H)基因突变的病例相比未突变的病例具有更好的生存率。也有报道称CLL中存在V(H)基因使用偏好，这可能反映了抗原选择。在对265例CLL病例的V(H)基因分析中，我们证实了V(H)突变状态的预后影响，并发现突变和未突变亚组中均存在V(H)基因使用偏好。有趣的是，重排一个特定V(H)基因V(H)3-21的CLL病例，尽管三分之二显示V(H)基因突变，但其预后较差。许多使用V(H)3-21的病例表达λ轻链，重排Vλ2-14基因，并具有同源互补决定区3（CDR3），这意味着识别共同的抗原表位。因此，我们认为重排V(H)3-21基因的病例构成了一个额外的CLL实体。我们进一步分析了346例CLL病例的V(H)基因重排，特别是重链CDR3序列，以研究抗原在CLL中的作用。我们鉴定出六个新的亚组，它们具有与使用V(H)3-21的组相似的HCDR3特征和受限的VL基因使用情况。我们的数据表明这些亚组中的抗原识别位点数量有限，并为CLL发生发展中的抗原选择提供了进一步证据。除了2%的阈值外，还使用了不同的突变阈值来区分突变型CLL。我们使用三个水平的体细胞突变将323例CLL分为生存情况不同的亚组（<2%、2-5%和>5%突变）。这种划分揭示了一个低突变亚组（突变率2-5%），其预后较差，而使用传统的2%阈值会掩盖这一情况。据报道，P2X(7)受体基因中的1513A/C多态性在CLL中更常见，但在我们的170例CLL病例和200例对照中未发现基因型频率的差异。然而，具有1513AC基因型的CLL病例比1513AA病例具有更好的生存率，这尤其局限于V(H)基因突变的CLL。总之，我们可以通过Ig基因重排分析在CLL中定义新的预后亚组。这也使我们能够深入了解CLL发病机制中抗原参与的生物学特性和潜在作用。
