Jardin Fabrice, Sahota Surinder S
Département d'Hématologie Clinique and Groupe d'étude des proliférations lymphoïdes, Centre Henri Becquerel, Rouen, France.
Hematology. 2005 Apr;10(2):115-29. doi: 10.1080/10245330400026105.
Cloning translocation breakpoints which cluster suspiciously to specific chromosomal loci has proved fruitful, leading to the identification of genes implicated in the onset of hematological malignancy. One of the most notable is BCL6, located on chromosome 3q27. The BCL6 is now known to encode a nuclear transcriptional repressor, with pivotal roles in germinal center (GC) formation and regulation of lymphocyte function, differentiation and survival. Unusually, the BCL6 gene locus is also actively targeted by the somatic mutation (SM) mechanism, at a rate indicative of specific, regulated events in both normal and malignant B-cells. These mutations occur in approximately 30% of normal centrocytes and centroblasts, but not in naive or pre-GC B-cells. They are also observed in approximately 70% of diffuse large B-cells lymphomas, approximately 30% of follicular lymphomas (FL) and at various frequencies in many lymphoma subtypes. Mutations are generated in the 5' proximity of the BCL6 promoter, including the first intron and are mainly single nucleotide substitutions, but with insertions and deletions also observed. Mutations in BCL6 occur independently of translocations, although mutational levels can be dramatically influenced by aberrantly translocated chromosomal elements, which map in the vicinity of the gene. Indeed, SMs are directly implicated in the generation of chromosomal translocations, as suggested by the overlap of the breakpoint cluster region and the mutational cluster domain. The prognostic value of the overall level of BCL6 mutations in specific lymphoma populations is, in the main, not as yet fully resolved. The accumulation of mutations in BCL6 during high grade transformation of FL, a mutational clustering and specific recurrent mutations suggest that some mutations may be selected for by their effect on the survival of the tumoral clone. In fact, it is now clear that SM can target and disrupt regulatory motifs in BCL6 to result in upregulated gene expression. Exogenous factors can also perturbate SM in BCL6. Viral infection elevates BCL6 mutational activity, suggesting a potential link with onset of virus-associated lymphoma. These findings to date reveal several mechanisms which can influence specific mutations targeting BCL6, and which may contribute to lymphomagenesis by dysregulating control of BCL6 expression.
克隆那些可疑地聚集在特定染色体位点的易位断点已被证明卓有成效，这使得与血液系统恶性肿瘤发病相关的基因得以鉴定。其中最著名的是位于3q27染色体上的BCL6。现在已知BCL6编码一种核转录抑制因子，在生发中心（GC）形成以及淋巴细胞功能、分化和存活的调节中起关键作用。不同寻常的是，BCL6基因位点也会被体细胞突变（SM）机制积极靶向，其发生率表明在正常和恶性B细胞中存在特定的、受调控的事件。这些突变大约发生在30%的正常中心细胞和中心母细胞中，但在幼稚或GC前B细胞中不发生。在大约70%的弥漫性大B细胞淋巴瘤、大约30%的滤泡性淋巴瘤（FL）以及许多淋巴瘤亚型中以不同频率也观察到这些突变。突变发生在BCL6启动子的5'端附近，包括第一个内含子，主要是单核苷酸替换，但也观察到插入和缺失。BCL6中的突变独立于易位发生，尽管突变水平会受到异常易位的染色体元件的显著影响，这些元件定位在该基因附近。实际上，正如断点簇区域和突变簇结构域的重叠所表明的，SM直接参与了染色体易位的产生。特定淋巴瘤群体中BCL6突变总体水平的预后价值在很大程度上尚未完全明确。在FL的高级别转化过程中BCL6突变的积累、突变聚类和特定的复发性突变表明，一些突变可能因其对肿瘤克隆存活的影响而被选择。事实上，现在很清楚SM可以靶向并破坏BCL6中的调控基序，从而导致基因表达上调。外源性因素也会干扰BCL6中的SM。病毒感染会提高BCL6的突变活性，这表明与病毒相关淋巴瘤的发病可能存在潜在联系。迄今为止的这些发现揭示了几种可以影响靶向BCL6的特定突变的机制，并且可能通过失调BCL6表达的控制而导致淋巴瘤发生。
