BACKGROUND: Anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma 
(ALK+ ALCL) is a T cell lymphoma defined by the presence of chromosomal 
translocations involving the ALK tyrosine kinase gene. These translocations 
generate fusion proteins (e.g. NPM-ALK) with constitutive tyrosine kinase 
activity, which activate numerous signalling pathways important for ALK+ ALCL 
pathogenesis. The molecular chaperone heat shock protein-90 (Hsp90) plays a 
critical role in allowing NPM-ALK and other signalling proteins to function in 
this lymphoma. Co-chaperone proteins are important for helping Hsp90 fold 
proteins and for directing Hsp90 to specific clients; however the importance of 
co-chaperone proteins in ALK+ ALCL has not been investigated. Our preliminary 
findings suggested that expression of the immunophilin co-chaperone, Cyclophilin 
40 (Cyp40), is up-regulated in ALK+ ALCL by JunB, a transcription factor 
activated by NPM-ALK signalling. In this study we examined the regulation of the 
immunophilin family of co-chaperones by NPM-ALK and JunB, and investigated 
whether the immunophilin co-chaperones promote the viability of ALK+ ALCL cell 
lines.
METHODS: NPM-ALK and JunB were knocked-down in ALK+ ALCL cell lines with siRNA, 
and the effect on the expression of the three immunophilin co-chaperones: Cyp40, 
FK506-binding protein (FKBP) 51, and FKBP52 examined. Furthermore, the effect of 
knock-down of the immunophilin co-chaperones, either individually or in 
combination, on the viability of ALK+ ALCL cell lines and NPM-ALK levels and 
activity was also examined.
RESULTS: We found that NPM-ALK promoted the transcription of Cyp40 and FKBP52, 
but only Cyp40 transcription was promoted by JunB. We also observed reduced 
viability of ALK+ ALCL cell lines treated with Cyp40 siRNA, but not with siRNAs 
directed against FKBP52 or FKBP51. Finally, we demonstrate that the decrease in 
the viability of ALK+ ALCL cell lines treated with Cyp40 siRNA does not appear 
to be due to a decrease in NPM-ALK levels or the ability of this oncoprotein to 
signal.
CONCLUSIONS: This is the first study demonstrating that the expression of 
immunophilin family co-chaperones is promoted by an oncogenic tyrosine kinase. 
Moreover, this is the first report establishing an important role for Cyp40 in 
lymphoma.