Expression of ZAP70 in CLL activates NF-κB signalling
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ABSTRACT: Chronic lymphocytic leukemia (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 (IgVH) 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 NF-κB target genes interleukin-1β (IL-1β), IL-6 and IL-8 upon BCR triggering. This could be blocked by inhibition of NF-κB signaling 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 signaling in CLL cells which could be an underlying mechanism for its association with poor prognosis and which may represent a therapeutic target.
ORGANISM(S): Homo sapiens
PROVIDER: GSE51286 | GEO | 2013/10/22
SECONDARY ACCESSION(S): PRJNA223276
REPOSITORIES: GEO
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