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Leukemia. 2015 Nov;29(11):2162-72. doi: 10.1038/leu.2015.127. Epub 2015 May 19.

Constitutive control of AKT1 gene expression by JUNB/CJUN in ALK+ anaplastic large-cell lymphoma: a novel crosstalk mechanism.

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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.
Wuxi Medical School and Affiliated Hospital, Jiangnan University, Wuxi, China.
Department of Pathology, Saint Jude Children's Hospital, Memphis, TN, USA.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Pathology and Cytology, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
Experimental Therapeutics Academic Program and Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.


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.

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