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
