The Myc-miR-17-92 axis amplifies B-cell receptor signaling via inhibition of ITIM proteins: a novel lymphomagenic feed-forward loop
The Myc-miR-17-92 axis amplifies B-cell receptor signaling via inhibition of ITIM proteins: a novel lymphomagenic feed-forward loop
复制标题
DOI：
10.1182/blood-2012-12-473090
复制
发表时间：
2013-12-19
期刊：
影响因子：
20.3
通讯作者：
Thomas-Tikhonenko, Andrei
中科院分区：
文献类型：
--
作者：
Psathas, James N.;Doonan, Patrick J.;Thomas-Tikhonenko, Andrei
c-Myc癌蛋白调节>15%的人类转录组和有限数量的microRNA（miRNA）。在这里，我们确定在人类B淋巴细胞系中，Myc抑制的，但不是Myc刺激的，基因显著富集了Myc调节的miRNA的预测结合位点，主要是那些包含Myc激活的miR-17类似于92簇的基因。值得注意的是，基因集富集分析表明，miR-17类似于92，是B细胞受体（BCR）途径组分的主要调节因子。其中许多是含有免疫受体酪氨酸抑制基序（ITIM）的蛋白，并且ITIM蛋白CD 22和FCGR 2B被发现是miR-17的直接靶点，类似于92。与ITIM蛋白募集磷酸酶的倾向一致，MYC或miR-17类似于92表达对于在BCR连接后维持脾酪氨酸激酶（SYK）和B细胞连接蛋白（BLNK）的磷酸化是必需的。在更下游，miR-17-92对BCR应答的刺激导致钙通量增强和Myc本身水平升高。值得注意的是，在弥漫性大B细胞淋巴瘤（DLBCL）细胞系中抑制类似于92簇的miR-17减少了BCR应答，如通过SYK和BLNK磷酸化测量的。相反，BCR亚型的人DLBCL表达比其他亚型更高的Myc和mir 17 hg转录水平。因此，Myc-miR-17-92-BCR轴，经常受到基因组重排的影响，构成了一个新的淋巴瘤前馈环。
The c-Myc oncoprotein regulates >15% of the human transcriptome and a limited number of microRNAs (miRNAs). Here, we establish that in a human B-lymphoid cell line, Myc-repressed, but not Myc-stimulated, genes are significantly enriched for predicted binding sites of Myc-regulated miRNAs, primarily those comprising the Myc-activated miR-17 similar to 92 cluster. Notably, gene set enrichment analysis demonstrates that miR-17 similar to 92 is a major regulator of B-cell receptor (BCR) pathway components. Many of them are immunoreceptor tyrosine inhibitory motif (ITIM)-containing proteins, and ITIM proteins CD22 and FCGR2B were found to be direct targets of miR-17 similar to 92. Consistent with the propensity of ITIM proteins to recruit phosphatases, either MYC or miR-17 similar to 92 expression was necessary to sustain phosphorylation of spleen tyrosine kinase (SYK) and the B-cell linker protein (BLNK) upon ligation of the BCR. Further downstream, stimulation of the BCR response by miR-17-92 resulted in the enhanced calcium flux and elevated levels of Myc itself. Notably, inhibition of the miR-17 similar to 92 cluster in diffuse large B-cell lymphoma (DLBCL) cell lines diminished the BCR response as measured by SYK and BLNK phosphorylation. Conversely, human DLBCLs of the BCR subtype express higher Myc and mir17hg transcript levels than other subtypes. Hence, the Myc-miR-17-92-BCR axis, frequently affected by genomic rearrangements, constitutes a novel lymphomagenic feed-forward loop.