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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.

Author information

1
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2
GP Livanos and M Simou Laboratories, First Department of Critical Care Medicine and Pulmonary Services, Medical School of Athens University, 'Evangelismos' Hospital, Athens, Greece.
3
Wuxi Medical School and Affiliated Hospital, Jiangnan University, Wuxi, China.
4
Department of Pathology, Saint Jude Children's Hospital, Memphis, TN, USA.
5
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6
Department of Pathology and Cytology, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
7
Experimental Therapeutics Academic Program and Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.

Abstract

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.

PMID:
25987255
PMCID:
PMC4633353
DOI:
10.1038/leu.2015.127
[Indexed for MEDLINE]
Free PMC Article

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