Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
Department of Clinical Medicine, University "Federico II" of Naples, Naples, Italy.
Cell Death Dis. 2018 Jan 9;9(1):13. doi: 10.1038/s41419-017-0026-3.
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.
慢性淋巴细胞白血病（CLL）是最常见的 B 细胞恶性肿瘤，其临床结局具有异质性。需要寻找 CLL 进展的生物标志物来优化预后和治疗。布鲁顿酪氨酸激酶同工型α（IBTKα）基因编码一种 Cullin 3 依赖性 E3 泛素连接酶的底物受体，可促进细胞在应对内质网应激时存活。为了寻找 CLL 进展的新型标志物，我们分析了 CLL 患者一线治疗缓解前后外周血 B 细胞中 IBTKα 的表达。在疾病进展时，IBTKα 的表达显著增加，而在化疗缓解后则减少。与促进生存的作用一致，IBTKα 的 RNA 干扰增加了 MEC-1 CLL 细胞的自发和氟达拉滨诱导的凋亡，并通过促进 G0/G1 期阻滞和凋亡来破坏 De Few B 淋巴瘤细胞的细胞周期。同样，IBTKα 的 RNA 干扰上调了促凋亡基因的表达，包括 TNF、CRADD、CASP7、BNIP3 和 BIRC3。我们的结果表明，IBTKα 是 CLL 进展的一个新的标志物，可促进细胞生长和抵抗凋亡。因此，IBTKα 可能代表一种有吸引力的癌症药物靶点，可用于对抗肿瘤细胞的治疗耐药性。
