Atsaves V, Zhang R, Ruder D, Pan Y, Leventaki V, Rassidakis G Z, Claret F X
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
GP Livanos and M Simou Laboratories, First Department of Critical Care Medicine and Pulmonary Services, Medical School of Athens University, 'Evangelismos' Hospital, Athens, Greece.
Leukemia. 2015 Nov;29(11):2162-72. doi: 10.1038/leu.2015.127. Epub 2015 May 19.
Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is an aggressive T-cell non-Hodgkin lymphoma characterized by the t(2;5), resulting in the overexpression of nucleophosmin (NPM)-ALK, which is known to activate the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, resulting in cell cycle and apoptosis deregulation. ALK+ ALCL is also characterized by strong activator protein-1 (AP-1) activity and overexpression of two AP-1 transcription factors, CJUN and JUNB. Here, we hypothesized that a biologic link between AP-1 and AKT kinase may exist, thus contributing to ALCL oncogenesis. We show that JUNB and CJUN bind directly to the AKT1 promoter, inducing AKT1 transcription in ALK+ ALCL. Knockdown of JUNB and CJUN in ALK+ ALCL cell lines downregulated AKT1 mRNA and promoter activity and was associated with lower AKT1 protein expression and activation. We provide evidence that this is a transcriptional control mechanism shared by other cell types even though it may operate in a way that is cell context-specific. In addition, STAT3 (signal transducer and activator of transcription 3)-induced control of AKT1 transcription was functional in ALK+ ALCL and blocking of STAT3 and AP-1 signaling synergistically affected cell proliferation and colony formation. Our findings uncover a novel transcriptional crosstalk mechanism that links AP-1 and AKT kinase, which coordinate uncontrolled cell proliferation and survival in ALK+ ALCL.
间变性淋巴瘤激酶阳性（ALK+）间变性大细胞淋巴瘤（ALCL）是一种侵袭性T细胞非霍奇金淋巴瘤，其特征为t(2;5)，导致核磷蛋白（NPM）-ALK过表达，已知该蛋白可激活磷脂酰肌醇-3激酶（PI3K）/AKT/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路，从而导致细胞周期和细胞凋亡失调。ALK+ ALCL的另一个特征是具有较强的活化蛋白-1（AP-1）活性以及两种AP-1转录因子CJUN和JUNB的过表达。在此，我们推测AP-1与AKT激酶之间可能存在生物学联系，这对ALCL的肿瘤发生具有促进作用。我们发现JUNB和CJUN可直接结合至AKT1启动子，在ALK+ ALCL中诱导AKT1转录。在ALK+ ALCL细胞系中敲低JUNB和CJUN可下调AKT1 mRNA及启动子活性，并与较低的AKT1蛋白表达和活化相关。我们提供的证据表明，这是一种其他细胞类型也共有的转录调控机制，尽管其作用方式可能具有细胞背景特异性。此外，信号转导及转录激活因子3（STAT3）诱导的对AKT1转录的调控在ALK+ ALCL中发挥作用，阻断STAT3和AP-1信号可协同影响细胞增殖和集落形成。我们的研究结果揭示了一种新的转录串扰机制，该机制将AP-1与AKT激酶联系起来，在ALK+ ALCL中协调不受控制的细胞增殖和存活。
