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.
Highlights
Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in Western countries with an incidence of 4.6 per 100,000 new cases per year (http:// www.who.int/selection_medicines/committees/expert/20/Official journal of the Cell Death Differentiation AssociationAlbano et al Cell Death and Disease (2018)9:13 mutations compared to germline[1,2]
The expression of Inhibitor of Bruton’s tyrosine kinase—isoform α (IBTKα) gene progressively increased in Binet A (p = 0.0005), Binet B (p < 0.0001) and Binet C (p < 0.0001) groups compared to healthy donors, with the highest expression in Binet C group (Fig. 1a)
Based on IGHV sequencing[22], ten CLL patients with the highest IBTKα expression (CLL 2, 3, 4, 5, 11, 14, 22, 25, 26, 31) belonged to the M-CLL subtype, which might explain the lack of up-regulation of Lipoprotein lipase (LPL), CD38 and Zeta-chainassociated protein kinase 70 (ZAP70) genes in our CLL samples
Summary
Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in Western countries with an incidence of 4.6 per 100,000 new cases per year (http:// www.who.int/selection_medicines/committees/expert/20/Official journal of the Cell Death Differentiation AssociationAlbano et al Cell Death and Disease (2018)9:13 mutations compared to germline[1,2]. The enhanced expression of CD38, Lipoprotein lipase (LPL) and Zeta-chainassociated protein kinase 70 (ZAP70) was associated to U-CLL with rapid fatal outcome[4,5,6,7]. These genes were not proved to be reliable biomarkers for evaluating the clinical course of CLL and the effectiveness of therapy. The 150 kDa IBtkα protein is the most abundant isoform that is highly expressed in B-lymphoid tissues[9,16] It acts as substrate receptor of the Cullin 3-
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