NOTCH2 links protein kinase C delta to the expression of CD23 in chronic lymphocytic leukaemia (CLL) cells

SummaryOne characteristic of chronic lymphocytic leukaemia (CLL) lymphocytes ishigh expression of CD23, which has previously been identified as adownstream target for NOTCH2 signalling. The mechanisms regulatingNOTCH2-dependent CD23 expression, however, are largely unknown. Thisstudy showed that peripheral CLL cells overexpressed transcriptionally activeNOTCH2 (N2 IC ), irrespective of their prognostic marker profile. Whenplaced in culture, NOTCH2 activity was spontaneously decreased in 25 out of31 CLL cases (81%) within 24 h. DNA-bound N2 IC complexes could bemaintained by the protein kinase C (PKC) activator phorbol 12-myristate13-acetate (PMA) or by c-interferon (IFN-c), two CLL characteristicinducers of CD23 expression. Inhibition of PKC-d by RNA interference orby rottlerin antagonised PMA-induced NOTCH2 activation and alsosuppressed NOTCH2 activity in CLL cases with constitutively activatedNOTCH2 signalling. In 23 out of 29 CLL cases tested (79%), DNA-boundN2 IC complexes were found to be resistant to the c-secretase inhibitor (GSI)DAPT, suggesting that GSIs will be only effective in a subset of CLL cases.These data suggest that deregulation of NOTCH2 signalling is criticallyinvolved in maintaining the malignant phenotype of CLL lymphocytes andpoint to a link between PKC-d and NOTCH2 signalling in the leukemic cells.Keywords: chronic lymphocytic leukaemia, CD23, NOTCH2, PKC-d, IFN-c.