Raghoebier S, Broos L, Kramer M H, van Krieken J H, Kluin-Nelemans J C, van Ommen G J, Kluin P
Laboratory of Pathology, University of Leiden, The Netherlands.
Leukemia. 1995 Oct;9(10):1748-55.
About half of the patients with follicular lymphoma will develop an aggressive B cell lymphoma with morphological changes in growth pattern and cellular morphology. Changes of the immunophenotype, especially of the expression of immunoglobulin (Ig) have been documented less frequently. Multiple tumor samples of two patients with follicular lymphoma who developed tumor progression, were studied by Southern blot analysis for rearrangements of the Ig genes and the oncogenes BCL2 and MYC. In both patients, the general pattern of Ig gene rearrangements, especially of the Ig light-chain genes, and the structure of the t(14;18) breakpoint as assessed by the polymerase chain reaction (PRC) and fine restriction mapping, remained unaltered with time. However, both within the functional Ig heavy-chain allele and around the t(14;18) breakpoint, extensive secondary alterations took place. This indicates clonal evolution rather than the appearance of an independent lymphoma. In the first case with progression from follicular lymphoma to Burkitt's lymphoma 3 years after diagnosis, alterations were especially present 3' of the t(14;18) breakpoint. In the second patient with a change from follicular to diffuse centroblastic lymphoma 4 years after diagnosis, subsequent class switches from IgM to IgG and to defective IgH expression were accompanied by deletion of C mu sequences and a rearrangement of the MYC gene, respectively. Additionally, in both patients alterations in individual restriction sites occurred, which most likely were due to somatic mutations within both the functional IgH and translocated allele. Our data indicate that complex alterations of both the functional and non-functional IgH allele may accompany tumor progression and may erroneously suggest the appearance of independent clones by Southern blot analysis. It remains to be established whether these alterations are causative events or the consequence of genetic instability and clonal evolution.
约半数滤泡性淋巴瘤患者会发展为侵袭性B细胞淋巴瘤，其生长模式和细胞形态会发生形态学改变。免疫表型的变化，尤其是免疫球蛋白（Ig）表达的变化，记录较少。对两名发生肿瘤进展的滤泡性淋巴瘤患者的多个肿瘤样本进行了Southern印迹分析，以研究Ig基因以及癌基因BCL2和MYC的重排情况。在两名患者中，Ig基因重排的总体模式，尤其是Ig轻链基因的重排模式，以及通过聚合酶链反应（PRC）和精细限制性图谱评估的t(14;18)断点结构，随时间保持不变。然而，在功能性Ig重链等位基因内部以及t(14;18)断点周围，发生了广泛的继发性改变。这表明是克隆进化而非出现了独立的淋巴瘤。在第一例患者中，诊断3年后从滤泡性淋巴瘤进展为伯基特淋巴瘤，t(14;18)断点下游3'处尤其出现了改变。在第二例患者中，诊断4年后从滤泡性淋巴瘤转变为弥漫性中心母细胞淋巴瘤，随后从IgM到IgG的类别转换以及有缺陷的IgH表达分别伴随着Cμ序列的缺失和MYC基因的重排。此外，两名患者的个别限制性位点均发生了改变，这很可能是由于功能性IgH和易位等位基因内的体细胞突变所致。我们的数据表明，功能性和非功能性IgH等位基因的复杂改变可能伴随肿瘤进展，并且可能通过Southern印迹分析错误地提示出现了独立克隆。这些改变是致病事件还是遗传不稳定和克隆进化的后果，仍有待确定。
