Pathologic and biologic study of extranodal lymphomas for the clarification of its molecular pathogenesis

近年来，人们对结外淋巴瘤的生物学行为，特别是粘膜相关淋巴组织（MALT）型的生物学行为非常感兴趣。t(11;18)（q21;q21）易位是MALT型低级别b细胞淋巴瘤的特征性染色体畸变。我们已经在MALT淋巴瘤患者中鉴定了一个YAC克隆y789F3，其断点位于18q21。在YAC上构建了BAC和PAC结构，发现BAC 193f9包含断点区域。我们利用BAC193f9构建的质粒群，通过FISH和Southern blot分析进一步缩小了5例MALT淋巴瘤患者在18q21处的断点区域。在5例MALT淋巴瘤患者中，有3例的18q21断点被发现大约聚集在20kb区域内。通过外显子扩增和cDNA文库筛选，我们在5例MALT淋巴瘤患者中的4例中发现了一个跨越断点区域的新cDNA，该区域表现出异常的mRNA信号。该核苷酸序列预测了一个813个氨基酸的蛋白，该蛋白与CD22β和层粘连蛋白5 α3b亚基具有显著的序列相似性。我们将编码该转录本的基因称为MALT1。MALT1易位改变强烈提示该基因在MALT淋巴瘤的发病机制中起重要作用。值得注意的是，其中，API2-MALT1基因表达的MALT淋巴瘤似乎构成了一个同质的疾病实体。显微镜下的外观足以明确诊断，或至少在常规切片中进行诊断。它们的解剖部位也倾向于肺、肠和不太常见的胃。此外，API2-MALT1基因改变的胃MALT淋巴瘤似乎与幽门螺杆菌感染无关。在以前的报道中，这组特征在这种独特的肿瘤中并没有得到充分的强调。

In a recent year, much interest is focused on the biologic behavior of extranodal lymphomas, especially of mucosa-associated lymphoid tissue (MALT) type. The t(11;18)(q21;q21) translocation is a characteristic chromosomal aberration in low-grade B-cell lymphoma of MALT type. We have identified a YAC clone y789F3, which includes the breakpoint at 18q21 in a MALT lymphoma patient. BAC and PAC contigs were constructed on the YAC, and BAC 193f9 was found to encompass the breakpoint region. We further narrowed down the breakpoint region at 18q21 in five MALT lymphoma patients by means of FISH and Southern blot analyses using the plasmid contig constructed from BAC193f9. The breakpoints at 18q21 in three of the five MALT lymphoma patients were found to be clustered approximately within the 20kb region. By using exon amplification and cDNA library screening, we identified a novel cDNA spanning the breakpoint region that exhibited aberrant mRNA signals in four of the five MALT lymphoma patients. The nucleotide sequence predicted an 813 amino acid protein that shows significant sequence similarity to the CD22β and laminin 5 α3b subunit. We refereed to the gene encoding this transcript as MALT1. The alteration of MALT1 by translocation strongly suggested that this gene plays an important role in the pathogenesis of MALT lymphoma. Notably, among them, MALT lymphoma with API2-MALT1 gene expression appeared to constitute a homogeneous disease entity. The microscopic appearance is distinctive enough for the diagnosis to be made or at least entertained in routine sections. Their anatomical sites also preferred to lung, intestine, and less commonly stomach. In addition, gastric MALT lymphoma with the genetic alteration of API2-MALT1 seemed to have no relationship with Helicobacter pylori infection. The presence of this set of features in this distinctive tumors has not been sufficiently emphasized in previous reports.