The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL
The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL
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DOI：
10.1038/leu.2015.114
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发表时间：
2015-05
期刊：
影响因子：
11.4
通讯作者：
Elena Vasyutina;Jorge Bouças;J. Bloehdorn;C. Aszyk;G. Crispatzu;Marius Stiefelhagen;A. Breuer;Petra Mayer;Claudia Lengerke;Hartmut Döhner;Dirk Beutner;Andreas Rosenwald;S. Stilgenbauer;Michael Hallek;A. Benner;Marco Herling
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文献类型：
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作者：
Elena Vasyutina;Jorge Bouças;J. Bloehdorn;C. Aszyk;G. Crispatzu;Marius Stiefelhagen;A. Breuer;Petra Mayer;Claudia Lengerke;Hartmut Döhner;Dirk Beutner;Andreas Rosenwald;S. Stilgenbauer;Michael Hallek;A. Benner;Marco Herling
失调的T细胞白血病/淋巴瘤-1A（TCL 1A）是B细胞受体（BCR）信号传导的调节剂，与慢性淋巴细胞白血病（CLL）有因果关系。然而，TCL 1A调控的机制在很大程度上是未知的。为了表征TCL 1A上游网络，我们功能性地筛选了TCL 1A抑制性微RNA（miR）及其转录调控因子。我们鉴定了新的miR-484靶向TCL 1A的3′-UTR，并在CLL中下调。在染色质免疫沉淀和报告基因测定中，髓样细胞的致癌转录因子EVI 1结合并激活miR-484启动子。在CLL中最常见的是泛EVI 1转录变体。EVI 1蛋白表达揭示了不同的正常组织和白血病相关的EVI 1/TCL 1A共调节模式。在TCL 1A-高CLL或此类细胞亚群中，EVI 1水平特别低。来自337名患者的全球基因表达谱通过TCL 1A、BTK和其他与CLL相关的分子将EVI 1网络与BCR信号传导和细胞存活联系起来。增强的EVI 1和miR-484一样，抑制了TCL 1A。此外，它降低了磷酸激酶水平，损害了细胞存活，减轻了BCR诱导的钙流，并减少了体外依鲁替尼反应。此外，在前瞻性治疗的患者中，TCL 1A和EVI 1显示出强烈的相互作用的危险预测。总体而言，我们提出回归EVI 1作为一种新的监管签名在慢性淋巴细胞白血病。通过增强的TCL 1A和CLL的其他EVI 1靶向标志，这有助于侵袭性细胞和临床表型。
Dysregulated T-cell leukemia/lymphoma-1A (TCL1A), a modulator in B-cell receptor (BCR) signaling, is causally implicated in chronic lymphocytic leukemia (CLL). However, the mechanisms of the perturbed TCL1A regulation are largely unknown. To characterize TCL1A-upstream networks, we functionally screened for TCL1A-repressive micro-RNAs (miRs) and their transcriptional regulators. We identified the novel miR-484 to target TCL1A’s 3′-UTR and to be downregulated in CLL. In chromatin immunoprecipitations and reporter assays, the oncogenic transcription factor of myeloid cells, EVI1, bound and activated the miR-484 promoter. Most common in CLL was a pan-EVI1 transcript variant. EVI1 protein expression revealed distinct normal-tissue and leukemia-associated patterns of EVI1/TCL1A co-regulation. EVI1 levels were particularly low in TCL1A-high CLL or such cellular subsets. Global gene expression profiles from a 337-patient set linked EVI1 networks to BCR signaling and cell survival via TCL1A, BTK and other molecules of relevance in CLL. Enforced EVI1, as did miR-484, repressed TCL1A. Furthermore, it reduced phospho-kinase levels, impaired cell survival, mitigated BCR-induced Ca-flux and diminished the in vitro ibrutinib response. Moreover, TCL1A and EVI1 showed a strongly interactive hazard prediction in prospectively treated patients. Overall, we present regressive EVI1 as a novel regulatory signature in CLL. Through enhanced TCL1A and other EVI1-targeted hallmarks of CLL, this contributes to an aggressive cellular and clinical phenotype.