Differentiation stage-specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas
Differentiation stage-specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas
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DOI：
10.1182/blood-2008-10-184077
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发表时间：
2009-04-16
期刊：
影响因子：
20.3
通讯作者：
Lossos, Izidore S.
中科院分区：
文献类型：
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作者：
Malumbres, Raquel;Sarosiek, Kristopher A.;Lossos, Izidore S.
MiRNAs是一种与靶转录产物3‘-UTR区的部分互补位点结合并抑制其表达的小RNA分子。MiRNAs协调多种细胞功能，并在细胞分化和癌症发展中发挥关键作用。我们分析了外周B细胞分化过程中B细胞亚群以及弥漫性大B细胞淋巴瘤(DLBCL)细胞中的miRNA图谱。我们的结果显示了B细胞分化过程中miRNA表达的时间变化，在生发中心(GC)淋巴细胞中具有高度独特的miRNA图谱。我们提供了这些变化可能与生理相关的实验证据，证明了GC丰富的hsa-miR-125b下调了IRF4和PRDM1/BLIMP1的表达，而记忆B细胞丰富的hsa-miR-223下调了LMO2的表达。我们进一步证明，尽管恶性细胞生物学的一个重要组成部分是从其未转化的细胞前体细胞-GC中心母细胞-遗传来的，但在细胞转化时获得了异常的miRNA表达。鉴定出一个9-miRNA特征，可以准确区分DLBCL的两个主要亚型。最后，这个信号中一些miRNAs的表达与统一治疗的DLBCL患者的临床结果相关。(血。2009；113：3754-3764)
miRNAs are small RNA molecules binding to partially complementary sites in the 3'-UTR of target transcripts and repressing their expression. miRNAs orchestrate multiple cellular functions and play critical roles in cell differentiation and cancer development. We analyzed miRNA profiles in B-cell subsets during peripheral B-cell differentiation as well as in diffuse large B-cell lymphoma (DLBCL) cells. Our results show temporal changes in the miRNA expression during B-cell differentiation with a highly unique miRNA profile in germinal center (GC) lymphocytes. We provide experimental evidence that these changes may be physiologically relevant by demonstrating that GC-enriched hsa-miR-125b down-regulates the expression of IRF4 and PRDM1/BLIMP1, and memory B cell-enriched hsa-miR-223 down-regulates the expression of LMO2. We further demonstrate that although an important component of the biology of a malignant cell is inherited from its nontransformed cellular progenitor-GC centroblasts-aberrant miRNA expression is acquired upon cell transformation. A 9-miRNA signature was identified that could precisely differentiate the 2 major subtypes of DLBCL. Finally, expression of some of the miRNAs in this signature is correlated with clinical outcome of uniformly treated DLBCL patients. (Blood. 2009; 113: 3754-3764)