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

ABSTRACT

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 γ-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, p21(WAF/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.