microRNA与弥漫大B 细胞淋巴瘤关系的研究进展

微小RNA（microRNA,miRNA）是一类长度为20多个核苷酸的内源性非编码调控RNA。它们通过序列特异性翻译抑制或mRNA 裂解来调控基因表达,参与细胞发育、增殖、分化、凋亡等一系列重要生物学过程。近期的研究发现,许多microRNA具有癌基因或抑癌基因的作用,在肿瘤的发生和发展中起着重要的作用。弥漫大B 细胞淋巴瘤（DLBCL）是最常见的一类恶性淋巴瘤,占非霍奇金淋巴瘤的30% 左右,DLBCL被定义为B 细胞起源的、有大的肿瘤细胞、具有侵袭性临床表现、需要高效力的化学治疗的恶性淋巴瘤,这类肿瘤发生于淋巴结内或结外,可原发或继发于其它低度恶性淋巴瘤的演进,临床表现、形态学、免疫表型及遗传学特征极具异质性。现已发现若干种microRNA直接参与弥漫大B 细胞淋巴瘤的发生和发展;microRNA表达谱也与弥漫大B 细胞淋巴瘤分子亚型相关。作为一类新的分子靶标,microRNA被应用于弥漫大B 细胞淋巴瘤的诊断和生物治疗具有广阔的前景。      

微小RNA与弥漫大B细胞淋巴瘤

微小RNA（miRNA）是一类小分子非编码RNA,通过与目标mRNA互补序列结合,在转录水平调控基因的表达。研究发现,包括弥漫大B细胞淋巴瘤在内的不同恶性肿瘤中存在特定的miRNA表达谱。因此,体液、组织标本中miRNA的表达将有望成为评估弥漫大B细胞淋巴瘤的新指标。     

微RNA与弥漫大B细胞淋巴瘤的相关性及其治疗应用研究进展

微RNA(miRNA)通过与靶标基因mRNA的3′非编码区结合, 在转录水平后调节基因的表达, 在弥漫大B细胞淋巴瘤(DLBCL)的发生中发挥重要作用。miRNA的表达水平与DLBCL的临床分期、分型、预后评估、治疗效果密切相关。miRNA具有作为DLBCL相关生物标志物的巨大潜力, 并且因两者之间的密切联系, 基于miRNA的治疗有望为DLBCL患者带来新的治疗方案。     

microRNA及其在淋巴瘤中的表达

 micro RNA（miRNA）是一类长度大约为22 nt的非编码小片段RNA，其进化保守，通过与mRNA的3'UTR相互作用进而调控mRNA的翻译，广泛作用于发育、炎症、凋亡和肿瘤等各个生物学过程。在T淋巴瘤中发现miR-106a和miR-17-92过度表达；在弥漫性大B细胞淋巴瘤和滤泡细胞淋巴瘤中的miR-155，miR-221和miR-21表达上调，并与肿瘤的亚型有关。miR-17 簇过度表达可使凋亡水平下降，表明这些miRNA的主要作用是抑制细胞的死亡。miRNA既可促进肿瘤的发生，又能抑制肿瘤，但其确切机制尚不明。随着研究的深入，miRNA的遗传表型调节功能将会越来越清楚。     

微小RNA与弥漫大B细胞淋巴瘤的关系及其作用

弥漫大B细胞淋巴瘤(DLBCL)是最常见的非霍奇金淋巴瘤,具有高度异质性.研究表明,微小RNA (miRNA)参与调控众多生物过程,与淋巴造血系统密切相关,并且在B细胞分化各阶段及其恶性转化过程中发挥重要作用.miRNA作为一种潜在的生物标志物日益受到关注,它与DLBCL的分型密切相关,对于该病的诊断具有重要价值,同时有助于判断不同患者的预后,并且可能成为新的治疗靶点.     

miRNA 和恶性肿瘤研究进展

microRNA（miRNA）是一类小RNA分子,在转录后水平对基因的表达进行调控。大量的证据显示绝大多数人类恶性肿瘤具有miRNA异常表型。miRNA与肿瘤中许多细胞过程如分化、增生和凋亡的改变有关。本文回顾了miRNA在肿瘤发生发展中的作用及其作为诊断、预后和治疗工具的可能性。      

LncRNA ZEB1⁃AS1对B细胞非霍奇金淋巴瘤增殖和凋亡的影响及其下游调控网络的分析

目的 探讨长链非编码 RNA（lncRNA） ZEB1-AS1对B 细胞非霍奇金淋巴瘤（B-cell non-Hodgkin's lymphoma,B-NHL）细胞增殖和凋亡的影响,构建lncRNA、miRNA、mRNA相关竞争性内源RNA（ceRNAs）网络。方法 采用Cox回归模型筛选GEO数据集（GSE31312）中与弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)预后相关的lncRNAs。采用慢病毒转染技术建立ZEB1-AS1敲低的B-NHL细胞模型,采用CCK-8法和流式细胞术分别检测敲低ZEB1-AS1及不同浓度（50 ng/mL、100 ng/mL、200 ng/mL、400 ng/mL）多柔比星（doxorubicin,Dox）处理后的细胞增殖与凋亡情况。构建以ZEB1-AS1为节点的 lncRNA-miRNA-mRNA ceRNA调控网络,利用GO、KEGG和PPI分析该调控网络下游相关的核心mRNA及其功能。结果 共筛选了20个高风险lncRNAs。预测与ZEB1-AS1有相互结合的miRNA 4个,与ZEB1-AS1呈共表达关系又与miRNA相结合的潜在下游mRNA 1 208个,以此构建lncRNA-miRNA-mRNA调控网络及PPI调控网络。在体外实验中,与空载组相比,敲低ZEB1-AS1可显著抑制细胞增殖和促进细胞凋亡（均P<0.05）,敲低ZEB1-AS1+Dox作用对抑制淋巴瘤细胞增殖和促进细胞凋亡有协同作用。结论  ZEB1-AS1敲低可抑制B-NHL细胞增殖和促进细胞凋亡,且可能增强Dox的药物敏感性;以ZEB1-AS1为节点构建的ceRNA调控网络,可能是DLBCL重要的调控机制和诊疗靶点。     

双重打击弥漫性大B 细胞淋巴瘤的临床病理研究进展

弥漫性大B 细胞淋巴瘤（diffuse large B-cell lymphoma,DLBCL ）是一种具有高度异质性的淋巴造血系统恶性肿瘤,目前用标准化疗方案治疗的多数DLBCL 患者可以被治愈,但仍有30% ～40% 的DLBCL 患者治疗后复发或难以治愈而死亡。双重打击淋巴瘤（double-hit lymphoma ,DHL ）主要发生于DLBCL 及介于DLBCL 和伯基特淋巴瘤（Burkitt's lymphoma ,BL）之间无法分类的B 细胞淋巴瘤（B-cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt's lymphoma ,BCLU）为生存期短、预后差、易复发的一种独特类型,是近年来的研究热点。虽然BCLU更容易发生DHL ,但DLBCL 是DHL 最常见的淋巴瘤,因此本文旨在对双重打击弥漫性大B 细胞淋巴瘤（double hit-DLBCL ,DH-DLBCL ）的流行病学和临床特征、诊断、分子遗传学及其治疗和预后特点等方面进行综述。      

miRNA在恶性血液病中的研究进展

 MicroRNA（miRNA）是一类小的非编码RNA,miRNA在转录水平介导目的基因mRNA的切割与翻译抑制,调控基因表达,调节细胞的增生、分化和凋亡,参与白血病、淋巴瘤的发生和进展。近年来,发现miRNA与恶性血液病的发生进展有关。通过不同的检测方法研究miRNA在恶性血液病中的表达,可对白血病、恶性淋巴瘤的发病机制更进一步了解,是诊断治疗和预后判断的重要指标。     

新的肿瘤标志物——循环微小RNA

微小RNA( microRNA,miRNA)是一类长约19～24 nt的非编码单链小RNA分子,转录后通过降解mRNA或者抑制翻译而调控蛋白的表达。miRNA 具有调控细胞周期、分化细胞等基本功能,并参与多种疾病的发生和发展。     

弥漫大B细胞淋巴瘤的分子靶向治疗

 弥漫大B细胞淋巴瘤（DLBCL）是最常见的成人非霍奇金淋巴瘤。现阶段利妥昔单抗与CHOP方案的联合应用已显著改善了DLBCL的预后,约50%的DLBCL可以治愈。然而由于肿瘤的异质性,对于难治、复发的DLBCL仍然缺乏行之有效的治疗方法。随着基因表达谱(GEP)的运用以及对淋巴瘤细胞内活化信号途径的深入研究,发现了很多潜在的治疗靶点。     

儿童侵袭性成熟B细胞淋巴瘤的临床病理学及分子遗传学特点

 目的　分析总结中国儿童各类型侵袭性成熟B细胞淋巴瘤的临床病理学及分子遗传学特点,为其诊断的标准化提供依据。方法　收集97例儿童侵袭性成熟B细胞淋巴瘤石蜡包埋组织标本,包括伯基特淋巴瘤（BL）81例、弥漫大B 细胞淋巴瘤（DLBCL）8例、介于BL和DLBCL间的不能分类的B细胞淋巴瘤（BL／DLBCL）8例,利用免疫组织化学技术和间期荧光原位杂交（FISH）技术检测其免疫表型和分子遗传学特征。结果　BL的bcl-2和MUM1的阳性率分别为3 %（2／66）和17 %（12／71）,DLBCL分别为50 %（4／8）和63 %（5／8）,BL／DLBCL分别为 50 %（4／8）和63 %（5／8）。BL、DLBCL 和BL／DLBCL 的Ki-67平均值分别为（93±4.4）%、（83±14.3）%和（80±11.5）%。BL、DLBCL 和BL／DLBCL 的c-myc 基因易位的比例分别为98 %（79／81）、38 %（3／8）和50 %（4／8）。38 %（3／8）的DLBCL和25 %（2／8）的BL／DLBCL 存在bcl-6基因的多拷贝,BL与DLBCL 之间、BL与BL／DLBCL之间bcl-2、MUM1和 Ki-67平均值的差异及c-myc基因易位和bcl-6基因多拷贝的差异均有统计学意义（均P＜0.05）。结论　儿童侵袭性成熟B细胞淋巴瘤的诊断和分型需要综合分析形态学、免疫表型和分子遗传学特征。儿童BL／DLBCL 可能是DLBCL 的一个亚型。CD+10、bcl-6+、bcl-2-、Ki-67＞90 %、伴有IGH／c-myc重排、不伴有bcl-2和bcl-6重排时,支持BL的诊断;bcl-2+、Ki-67 为50 %～90 %,同时伴有bcl-6基因的多拷贝时,支持 DLBCL或BL／DLBCL 的诊断。     

Role of microRNAs and microRNA machinery in the pathogenesis of diffuse large B-cell lymphoma

Deregulation of microRNA (miRNA) expression has been documented in diffuse large B-cell lymphoma (DLBCL). However, the impact of miRNAs and their machinery in DLBCL is not fully determined. Here, we assessed the role of miRNA expression and their processing genes in DLBCL development. Using microarray and RT-qPCR approaches, we quantified global miRNAs and core components of miRNA-processing genes expression in 75 DLBCLs (56 de novo and 19 transformed) and 10 lymph nodes (LN). Differential miRNA signatures were identified between DLBCLs and LNs, or between the de novo and transformed DLBCLs. We also identified subsets of miRNAs associated with germinal center B-cell phenotype, BCL6 and IRF4 expression, and clinical staging. In addition, we showed a significant over-expression of TARBP2 in de novo DLBCLs as compared with LNs, and decreased expression of DROSHA, DICER, TARBP2 and PACT in transformed as compared with de novo cases. Interestingly, cases with high TARBP2 and DROSHA expression had a poorer chemotherapy response. We further showed that TARBP2 can regulate miRNA-processing efficiency in DLBCLs, and its expression inhibition decreases cell growth and increases apoptosis in DLBCL cell lines. Our findings provide new insights for the understanding of miRNAs and its machinery in DLBCL.     

Diffuse Large B Cell Lymphoma Arising in Patients with Preexisting Hodgkin Lymphoma

The metachronic onset of diffuse large B-cell lymphoma (DLBCL) after classic Hodgkin lymphoma (cHL) is a rare event affecting patients’ outcomes. However, although several studies have investigated the prognostic role of this event, little is known about a hypothetical common origin of the two different neoplastic cells. Aims: To investigate a possible relationship between DLBCL and cHL, in this retrospective study of 269 patients with newly diagnosed cHL treated at Bari University Hospital (Italy) between 2007 and 2020, we analyzed data from 4 patients (3 male and 1 female) with cHL who subsequently developed DLBCL. Methods: Gene expression profile analysis, assessed by NanoString Lymphoma Subtype Assay, was performed to identify the cell of origin in the DLBCL cases, in addition to Hans’s algorithm. Results: Using Hans’s algorithm, all DLBCL cases showed a germinal center-B-Cell subtype. The gene expression profile evaluated by the NanoString Lymphoma Subtype Assay revealed two cases of the GCB molecular subtype, while the others were unclassified. After first-line chemotherapy, 1 patient achieved complete remission, 3 were non-responders (2 died of lymphoma within 6 months, whereas the other achieved complete remission after autologous and allogeneic stem cell transplantation and is still alive). Conclusions: The origin of the second neoplastic cell in patients with DLBCL with a previous history of cHL remains controversial, although the different immunophenotypic characteristics suggest that it may mainly arise de novo in a subject with a possible individual predisposition to develop lymphoid neoplasms.     

miR-320d与弥漫大B细胞淋巴瘤预后的相关性研究

目的 探讨miR-320d表达与弥漫大B细胞淋巴瘤（DLBCL）预后的关系.方法 应用EnVision法对山西省肿瘤医院有随访资料的原发于淋巴结的DLBCL 62例石蜡标本进行CD20、CD3、CD10、bcl-6、Mum-1免疫标记检测,根据Hans分类方法将DLBCL分为生发中心B细胞（GCB）型和非生发中心B细胞（non-GCB）型.采用安捷伦16.0高密度芯片对24例DLBCL石蜡标本进行miRNA表达谱筛选,用实时荧光定量PCR方法对62例DLBCL石蜡标本进行miR-320d表达验证.将1 1例淋巴结反应性增生标本作为对照.结果 62例DLBCL中,GCB型22例（35.5％）,non-GCB型40例（64.5％）,GCB型miR-320d表达水平是non-GCB型的3.43倍（P=0.034）.miR-320d在对照组的表达量是DLBCL的5.65倍（P＜ 0.001）.单因素分析示DLBCL中miR-320d低表达组总生存期低于高表达组,差异有统计学意义（P=0.021）.多因素Cox回归模型分析示62例DLBCL中,miR-320d低表达（RR=2.434,95％CI1.148～5.159,P=0.020）为独立于国际预后指数（IPI）的预后不良因素.结论 miR-320d表达下调预示DLBCL预后不良.     

Expression of Myc target gene mina53 in subtypes of human lymphoma

Mina53 (mina) was identified as a gene, which is directly induced by the oncogene c-myc. Elevated expression of Mina53 protein was found in >80% of colon cancer and esophageal squamous cell carcinoma (ESCC). Patients with high expression of Mina53 had shorter survival, suggesting the prognostic usefulness of Mina53. We studied Mina53 expression in lymphoma subtypes to examine its diagnostic significance and its possible role in lymphoma-genesis. Surgical cases of 28 lymphoma and 4 non-neoplastic tissues were stained immunochemically using anti-Mina53 monoclonal antibody. Mina53 expression correlated well with c-Myc expression in lymphoma, suggesting that c-Myc is a controlling factor for mina53 expression also in lymphomas. Although the expression of Mina53 as well as c-Myc was less frequent in lymphoma compared with those of colon and ESCC, increased expression of Mina53 was found in Burkitt-like lymphoma (1/1), Hodgkin's lymphoma (3/5), diffuse large B cell lymphoma (DLBCL) (5/13), lymphomas with a transition from follicular to DLBCL (1/2), with none in follicular (0/4) and T cell lymphoma (0/3). Analyses of the data suggested that Mina53 was frequently expressed in aggressive types of B cell lymphoma. To get more information about the expression of Mina53 in DLBCL, which most frequently occurs among lymphomas, we analyzed the expression of Mina53 in another 21 DLBCL specimens, which were in more advanced stages than those described above. The expression level of Mina53 correlated to the international prognostic index (IPI) values with statistical significance (r=0.477, P=0.0275). Notably, in this group, Mina53 expression did not correlate with c-Myc expression, suggesting that other factor(s) besides c-Myc largely affect the expression of Mina53 in advanced DLBCL. These results suggest that although Mina53 expression is not prominent in lymphoma in general, it may be related to tumor progression of B cell lymphoma.