Laffan M, Luzzatto L
Department of Haematology, Royal Postgraduate Medical School, London, United Kingdom.
J Clin Invest. 1992 Dec;90(6):2299-303. doi: 10.1172/JCI116117.
Discrete rearrangements of immunoglobulin genes are characteristic of lymphoproliferative diseases of B cells and provide direct evidence of their clonal nature. In addition, because leukemic transformation and growth may amplify B cell clones regardless of selection by antigen, analysis of rearranged Ig genes in leukemic clones may give insight into molecular events taking place during the ontogenesis of normal B cells. We have tested DNA samples from patients with chronic B cell leukemias in search for abnormal rearrangements of the Ig heavy chain gene region. By Southern blot analysis we found an unexpected break in the JH-C mu region in 7 out of 118 cases. Two of these cases were investigated in detail by constructing from each a phage genomic library and isolating the phage clones containing the break points. In both cases the JH-C mu separation was confirmed. Further analysis demonstrated that in both cases the abnormality was an inversion of the Ig heavy chain gene between C mu and one of the C gamma segments. This inversion structure strongly suggests that, as has been demonstrated in murine cell lines and in splenocytes stimulated in vitro, class switching in human B lymphocytes occurs in vivo via a loop-out deletion mechanism. The frequency of abnormal events may be as high as 15%. Our data indicate that a proportion of cases of chronic B cell leukemia arise from a cell which has attempted an Ig class switch.
免疫球蛋白基因的离散重排是B细胞淋巴增殖性疾病的特征，为其克隆性质提供了直接证据。此外，由于白血病转化和生长可能会扩增B细胞克隆，而不考虑抗原选择，因此分析白血病克隆中重排的Ig基因可能有助于深入了解正常B细胞个体发生过程中发生的分子事件。我们检测了慢性B细胞白血病患者的DNA样本，以寻找Ig重链基因区域的异常重排。通过Southern印迹分析，我们在118例病例中的7例中发现了JH-Cμ区域的意外断裂。其中两例通过从每个病例构建噬菌体基因组文库并分离包含断点的噬菌体克隆进行了详细研究。在这两个病例中，JH-Cμ分离均得到证实。进一步分析表明，在这两个病例中，异常均为Ig重链基因在Cμ和一个Cγ片段之间的倒位。这种倒位结构强烈表明，正如在小鼠细胞系和体外刺激的脾细胞中所证明的那样，人类B淋巴细胞中的类别转换在体内通过环出缺失机制发生。异常事件的频率可能高达15%。我们的数据表明，一部分慢性B细胞白血病病例源于尝试进行Ig类别转换的细胞。
