Laboratory of Molecular Immunobiology, Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.
Mol Med. 2013 May 20;19(1):115-23. doi: 10.2119/molmed.2013.00005.
Critical processes of B-cell physiology, including immune signaling through the B-cell receptor (BcR) and/or Toll-like receptors (TLRs), are targeted by microRNAs. With this in mind and also given the important role of BcR and TLR signaling and microRNAs in chronic lymphocytic leukemia (CLL), we investigated whether microRNAs could be implicated in shaping the behavior of CLL clones with distinct BcR and TLR molecular and functional profiles. To this end, we examined 79 CLL cases for the expression of 33 microRNAs, selected on the following criteria: (a) deregulated in CLL versus normal B-cells; (b) differentially expressed in CLL subgroups with distinct clinicobiological features; and, (c) if meeting (a) + (b), having predicted targets in the immune signaling pathways. Significant upregulation of miR-150, miR-29c, miR-143 and miR-223 and downregulation of miR-15a was found in mutated versus unmutated CLL, with miR-15a showing the highest fold difference. Comparison of two major subsets with distinct stereotyped BcRs and signaling signatures, namely subset 1 [IGHV1/5/7-IGKV1(D)-39, unmutated, bad prognosis] versus subset 4 [IGHV4-34/IGKV2-30, mutated, good prognosis] revealed differences in the expression of miR-150, miR-29b, miR-29c and miR-101, all down-regulated in subset 1. We were also able to link these distinct microRNA profiles with cellular phenotypes, importantly showing that, in subset 1, miR-101 downregulation is associated with overexpression of the enhancer of zeste homolog 2 (EZH2) protein, which has been associated with clinical aggressiveness in other B-cell lymphomas. In conclusion, specific miRNAs differentially expressed among CLL subgroups with distinct BcR and/or TLR signaling may modulate the biological and clinical behavior of the CLL clones.
B 细胞生理学的关键过程，包括通过 B 细胞受体（BcR）和/或 Toll 样受体（TLRs）进行免疫信号传递，都受到 microRNAs 的靶向调控。考虑到这一点，以及 BcR 和 TLR 信号传递以及 microRNAs 在慢性淋巴细胞白血病（CLL）中的重要作用，我们研究了 microRNAs 是否可能参与塑造具有不同 BcR 和 TLR 分子和功能特征的 CLL 克隆的行为。为此，我们检查了 79 例 CLL 病例中 33 种 microRNAs 的表达情况，这些 microRNAs是根据以下标准选择的：(a) 在 CLL 与正常 B 细胞相比中失调；(b) 在具有不同临床生物学特征的 CLL 亚组中差异表达；和，(c) 如果符合(a) + (b)，则在免疫信号通路中具有预测的靶标。在突变型 CLL 中发现 miR-150、miR-29c、miR-143 和 miR-223 的上调和 miR-15a 的下调，miR-15a 的倍数差异最大。比较具有不同定型 BcR 和信号特征的两个主要亚群，即亚群 1[IGHV1/5/7-IGKV1(D)-39，未突变，预后不良]与亚群 4[IGHV4-34/IGKV2-30，突变，预后良好]，发现 miR-150、miR-29b、miR-29c 和 miR-101 的表达存在差异，在亚群 1 中均下调。我们还能够将这些不同的 microRNA 谱与细胞表型联系起来，重要的是表明，在亚群 1 中，miR-101 的下调与增强子的过表达相关 2 同源物（EZH2）蛋白，这与其他 B 细胞淋巴瘤的临床侵袭性有关。总之，在具有不同 BcR 和/或 TLR 信号的 CLL 亚群中差异表达的特定 microRNAs 可能调节 CLL 克隆的生物学和临床行为。
