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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lymphoma, Large-Cell, Anaplastic / genetics*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-jun / physiology*
  • Receptor Protein-Tyrosine Kinases / analysis*
  • STAT3 Transcription Factor / physiology
  • Transcription Factor AP-1 / physiology
  • Transcription Factors / physiology*


  • JunB protein, human
  • Proto-Oncogene Proteins c-jun
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Transcription Factor AP-1
  • Transcription Factors
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt