The mechanisms of malignant cell transformation caused by the oncogenic, chimeric
nucleophosmin (NPM)/
anaplastic lymphoma kinase (ALK) remain only partially understood, with most of the previous studies focusing mainly on the impact of
NPM/ALK on cell survival and proliferation. Here we report that the
NPM/ALK-carrying
T cell lymphoma (ALK+TCL) cells strongly express the immunosuppressive
cell-surface protein CD274 (PD-L1, B7-H1), as determined on the
mRNA and
protein level. The CD274 expression is strictly dependent on the expression and enzymatic activity of
NPM/ALK, as demonstrated by inhibition of the
NPM/ALK function in ALK+TCL cells by the small molecule ALK inhibitor
CEP-14083 and by documenting CD274 expression in IL-3-depleted BaF3 cells transfected with the wild-type
NPM/ALK, but not the
kinase-inactive
NPM/ALK K210R mutant or empty vector alone.
NPM/ALK induces CD274 expression by activating its key signal transmitter,
transcription factor STAT3. STAT3 binds to the CD274 gene promoter in vitro and in vivo, as shown in the gel electromobility shift and
chromatin immunoprecipitation assays, and is required for the PD-L1 gene expression, as demonstrated by
siRNA-mediated STAT3 depletion. These findings identify an additional cell-transforming property of
NPM/ALK and describe a direct link between an
oncoprotein and an immunosuppressive
cell-surface protein. These results also provide an additional rationale to therapeutically target
NPM/ALK and STAT3 in ALK+TCL. Finally, they suggest that future immunotherapeutic protocols for this type of
lymphoma may need to include the inhibition of
NPM/ALK and STAT3 to achieve optimal clinical efficacy.