Expression of ZAP70 in chronic lymphocytic leukaemia activates NF-κB signalling.
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 (ZAP70). The reason why ZAP70 expression is associated with poor prognosis and whether the protein has a direct pathogenic function is at present unknown. By transfer of ZAP70 to CLL cells, we show here that expression of ZAP70 in CLL cells leads to increased expression of the nuclear factor (NF)-κB target genes interleukin-1β (IL1B), IL6 and IL8 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 ZAP70 expression in BCR-stimulated CLL cells. We conclude that ZAP70 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.
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
Valerie
V
Pede
Ans
A
Rombout
Jolien
J
Vermeire
Evelien
E
Naessens
Hanne
H
Vanderstraeten
Jan
J
Philippé
Bruno
B
Verhasselt
D000328:Adult; D000368:Aged; D020013:Calcium Signaling; D018274:Electroporation; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011379:Prognosis; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D051996:Transcription Factor RelA / Q000502:physiology; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; C508600:IL6 protein, human; D007093:Imidazoles; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D007378:Interleukins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011810:Quinoxalines; C498143:RELA protein, human; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D011993:Recombinant Fusion Proteins; D051996:Transcription Factor RelA; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D051550:I-kappa B Kinase
B-cell receptor; chronic lymphocytic leukaemia; nuclear factor-κB; zeta-associated protein of 70