The expression of inhibitor of bruton's tyrosine kinase gene is progressively up regulated in the clinical course of chronic lymphocytic leukaemia conferring resistance to apoptosis

Abstract

Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy with a variable clinical outcome. Biomarkers of CLL progression are required for optimising prognosis and therapy. The Inhibitor of Bruton's tyrosine kinase-isoform α (IBTKα) gene encodes a substrate receptor of Cullin 3-dependent E3 ubiquitin ligase, and promotes cell survival in response to the reticulum stress. Searching for novel markers of CLL progression, we analysed the expression of IBTKα in the peripheral blood B-cells of CLL patients, before and after first line therapy causing remission. The expression of IBTKα was significantly increased in disease progression, and decreased in remission after chemotherapy. Consistently with a pro-survival action, RNA interference of IBTKα increased the spontaneous and Fludarabine-induced apoptosis of MEC-1 CLL cells, and impaired the cell cycle of DeFew B-lymphoma cells by promoting the arrest in G0/G1 phase and apoptosis. Consistently, RNA interference of IBTKα up regulated the expression of pro-apoptotic genes, including TNF, CRADD, CASP7, BNIP3 and BIRC3. Our results indicate that IBTKα is a novel marker of CLL progression promoting cell growth and resistance to apoptosis. In this view, IBTKα may represent an attractive cancer drug target for counteracting the therapy-resistance of tumour cells.