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Expression of ZAP 70 in chronic lymphocytic leukaemia activates NF ‐κB signalling
Author(s) -
Pede Valerie,
Rombout Ans,
Vermeire Jolien,
Naessens Evelien,
Vanderstraeten Hanne,
Philippé Jan,
Verhasselt Bruno
Publication year - 2013
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12588
Subject(s) - zap70 , ighv@ , biology , breakpoint cluster region , chronic lymphocytic leukemia , cancer research , immunology , microbiology and biotechnology , t cell , il 2 receptor , receptor , immune system , leukemia , genetics
Summary Chronic lymphocytic leukaemia ( CLL ) is a disease with a highly variable prognosis. The clinical course can however be predicted thanks to prognostic markers. Poor prognosis is associated with expression of a B cell receptor ( BCR ) from unmutated immunoglobulin variable heavy‐chain genes ( IGHV ) and expression of zeta‐associated protein of 70 kDa ( ZAP 70). The reason why ZAP 70 expression is associated with poor prognosis and whether the protein has a direct pathogenic function is at present unknown. By transfer of ZAP 70 to CLL cells, we show here that expression of ZAP 70 in CLL cells leads to increased expression of the nuclear factor ( NF )‐κB target genes interleukin‐1β ( IL1B ), IL 6 and IL 8 upon BCR triggering. This could be blocked by inhibition of NF ‐κB signalling through inhibition of IκB kinases ( IKK ). Transcriptome analysis identified a NF ‐κB RELA signature imposed by ZAP 70 expression in BCR ‐stimulated CLL cells. We conclude that ZAP 70 acts directly as an amplifier of NF ‐κB signalling in CLL cells which could be an underlying mechanism for its association with poor prognosis and which may represent a therapeutic target.