Notch signalling in primary cutaneous CD30+lymphoproliferative disorders: a new therapeutic approach?

P>Background The oncogenic potential of deregulated Notch signalling has been described in several haematopoietic malignancies. We have previously reported an increased expression of Notch1 in primary cutaneous CD30+ lymphoproliferative disorders, lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma (pcALCL). Objectives To investigate the functional importance of Notch signalling in cell lines derived from pcALCL. Methods Cell lines derived from pcALCL (Mac1, Mac2a and JK) were treated with different gamma-secretase inhibitors (GSIs) (GSI I, IX, XX and XXI). The effects of GSIs on cell viability, apoptosis and cell cycle progression were measured as well as the impact of GSI I on the known prosurvival pathway Akt-mTOR-FOXO3a. Results Notch family members were expressed in all investigated pcALCL cell lines. GSI I had a marked proapoptotic effect, but GSI IX, XX and XXI were much less potent. The GSI I-triggered apoptosis was preceded by an accumulation of cells in the G2/M, cyclin B1-controlled phase of the cell cycle accompanied by an increase in the cyclin-dependent kinase inhibitor, p21WAF/Cip. GSI I induced the nuclear translocation of proapoptotic FOXO3a, probably via an Akt-independent pathway. Conclusions Notch signalling may be a future therapeutic target for the treatment of advanced pcALCL.