文章：

滤泡性淋巴瘤中BCL2的肿瘤间和肿瘤内异质性与IgH表达和预后相关

Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma

原文发布日期：2014-10-10

DOI: 10.1038/bcj.2014.67

类型: Original Article

开放获取: 是

英文摘要：

Most follicular lymphomas (FLs) are genetically defined by the t(14;18)(q32;q21) translocation that juxtaposes the BCL2 gene to the immunoglobulin heavy chain (IgH) 3' regulatory regions (IgH-3'RRs). Despite this recurrent translocation, FL cases are heterogeneous in terms of intratumoral clonal diversity for acquired mutations and variations in the tumor microenvironment. Here we describe an additional mechanism that contributes to inter- and intratumoral heterogeneity in FLs. By applying a novel single-molecule RNA fluorescence-based in situ hybridization (FISH) technique to detect mRNA molecules of BCL2 and IgH in single cells, we found marked heterogeneity in the number of BCL2 mRNA transcripts within individual lymphoma cells. Moreover, BCL2 mRNA molecules correlated with IgH mRNA molecules in individual cells both in t(14;18) lymphoma cell lines and in patient samples. Consistently, a strong correlation between BCL2 and IgH protein levels was found in a series of 205 primary FL cases by flow cytometry and immunohistochemistry. Inter- and intratumoral heterogeneity of BCL2 expression determined resistance to drugs commonly used in FL treatment and affected overall survival of FL patients. These data demonstrate that BCL2 and IgH expressions are heterogeneous and coregulated in t(14;18)-translocated cells, and determine the response to therapy in FL patients.

摘要翻译： 

大多数滤泡性淋巴瘤（FL）在遗传学上由t(14;18)(q32;q21)易位定义，该易位使BCL2基因与免疫球蛋白重链（IgH）3'调控区（IgH-3'RRs）并列。尽管存在这种重复性易位，但FL病例在获得性突变的肿瘤内克隆多样性和肿瘤微环境变化方面存在异质性。在此，我们描述了一种导致FL肿瘤间和肿瘤内异质性的额外机制。通过应用新型单分子RNA荧光原位杂交技术检测单个细胞中BCL2和IgH的mRNA分子，我们发现单个淋巴瘤细胞内的BCL2 mRNA转录本数量存在显著异质性。此外，在t(14;18)淋巴瘤细胞系和患者样本中，单个细胞内的BCL2 mRNA分子与IgH mRNA分子呈正相关。一致地，在205例原发性FL病例系列中，通过流式细胞术和免疫组织化学检测发现BCL2与IgH蛋白水平呈强相关性。BCL2表达的肿瘤间和肿瘤内异质性决定了FL常用治疗药物的耐药性，并影响FL患者的总生存期。这些数据表明，在t(14;18)易位细胞中，BCL2和IgH的表达具有异质性且存在协同调控，并决定了FL患者对治疗的反应。

原文链接：

Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma