MYC translocation-negative classical Burkitt lymphoma cases: an alternative pathogenetic mechanism involving miRNA deregulation
MYC translocation-negative classical Burkitt lymphoma cases: an alternative pathogenetic mechanism involving miRNA deregulation
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DOI：
10.1002/path.2410
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发表时间：
2008-12-01
影响因子：
7.3
通讯作者：
Leoncini, L.
中科院分区：
文献类型：
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作者：
Leucci, E.;Cocco, M.;Leoncini, L.
伯基特淋巴瘤（Burkitt lymphoma，BL）的分子特征是c-Myc易位，将其置于免疫球蛋白基因调控元件的控制之下。然而，越来越多的证据表明，一些病例可能缺乏可识别的MYC易位。此外，在EUROFISH项目中，旨在规范FISH程序在淋巴瘤诊断中的应用，我们发现，通过使用分裂信号和双融合探针，35例典型地方性BL中有5例MYC易位为阴性。在这里，我们研究了预测靶向c-Myc的miRNA在BL病例中的表达模式，以澄清在缺乏MYC易位的病例中，替代的发病机制是否可能是淋巴瘤发生的原因。miRNA是一类能够在转录后水平调节基因表达的小RNA。几项研究报告了它们与癌症的关系以及它们与基因组中脆弱位点的关系。它们还被证明可以控制细胞生长、分化和凋亡，这表明这些分子可以作为肿瘤抑制因子或致癌基因。我们的研究结果表明了特定的miRNAs的调节。特别地，与正常对照相比，在BL病例中观察到hsa-let-7 c的下调。更有趣的是，发现hsa-mir-34 b仅在MYC易位阴性的BL病例中下调，这表明该事件可能是此类病例中c-Myc失调的原因。我们的体外实验进一步证实了这一假设，该实验表明，增加剂量的合成hsa-mir-34 b能够调节c-Myc表达。这些结果首次表明，hsa-mir-34 b可能会影响伯基特淋巴瘤中c-Myc的表达，作为免疫球蛋白增强子基因座行使的更常见的异常控制。版权所有（C）2008大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
The molecular feature of Burkitt lymphoma (BL) is the translocation that places c-Myc under the control of immunoglobulin gene regulatory elements. However, there is accumulating evidence that some cases may lack an identifiable MYC translocation. In addition, during the EUROFISH project, aiming at the standardization of FISH procedures in lymphoma diagnosis, we found that five cases out of 35 classic endemic BLs were negative for MYC translocations by using a split-signal as well as a dual-fusion probe. Here we investigated the expression pattern of miRNAs predicted to target c-Myc, in BL cases, to clarify whether alternative pathogenetic mechanisms may be responsible for lymphomagenesis in cases lacking the MYC translocation. miRNAs are a class of small RNAs that are able to regulate gene expression at the post-transcriptional level. Several studies have reported their involvement in cancer and their association with fragile sites in the genome. They have also been shown to control cell growth, differentiation, and apoptosis, suggesting that these molecules could act as tumour suppressors or oncogenes. Our results demonstrated a modulation of specific miRNAs. In particular, down-regulation of hsa-let-7c was observed in BL cases, compared to normal controls. More interestingly, hsa-mir-34b was found to be down-regulated only in BL cases that were negative for MYC translocation, suggesting that this event might be responsible for c-Myc deregulation in such cases. This hypothesis was further confirmed by our in vitro experiments, which demonstrated that increasing doses of synthetic hsa-mir-34b were able to modulate c-Myc expression. These results indicate for the first time that hsa-mir-34b may influence c-Myc expression in Burkitt lymphoma as the more common aberrant control exercised by the immunoglobulin enhancer locus. Copyright (C) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.