Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, Québec, QC, Canada.
Division of Hematology and Hemostaseology, Department of Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Br J Cancer. 2020 Jul;123(2):240-251. doi: 10.1038/s41416-020-0887-6. Epub 2020 May 18.
High UGT2B17 is associated with poor prognosis in untreated chronic lymphocytic leukaemia (CLL) patients and its expression is induced in non-responders to fludarabine-containing regimens. We examined whether UGT2B17, the predominant lymphoid glucuronosyltransferase, affects leukaemic drug response and is involved in the metabolic inactivation of anti-leukaemic agents.
Functional enzymatic assays and patients' plasma samples were analysed by mass-spectrometry to evaluate drug inactivation by UGT2B17. Cytotoxicity assays and RNA sequencing were used to assess drug response and transcriptome changes associated with high UGT2B17 levels.
High UGT2B17 in B-cell models led to reduced sensitivity to fludarabine, ibrutinib and idelalisib. UGT2B17 expression in leukaemic cells involved a non-canonical promoter and was induced by short-term treatment with these anti-leukaemics. Glucuronides of both fludarabine and ibrutinib were detected in CLL patients on respective treatment, however UGT2B17 conjugated fludarabine but not ibrutinib. AMP-activated protein kinase emerges as a pathway associated with high UGT2B17 in fludarabine-treated patients and drug-treated cell models. The expression changes linked to UGT2B17 exposed nuclear factor kappa B as a key regulatory hub.
Data imply that UGT2B17 represents a mechanism altering drug response in CLL through direct inactivation but would also involve additional mechanisms for drugs not inactivated by UGT2B17.
高表达 UGT2B17 与未经治疗的慢性淋巴细胞白血病（CLL）患者预后不良相关，并且在对包含氟达拉滨的方案无反应者中其表达被诱导。我们研究了主要的淋巴葡萄糖醛酸基转移酶 UGT2B17 是否影响白血病药物反应，以及是否参与抗白血病药物的代谢失活。
通过质谱分析功能酶学测定和患者的血浆样本，评估 UGT2B17 对药物的失活作用。细胞毒性测定和 RNA 测序用于评估与高 UGT2B17 水平相关的药物反应和转录组变化。
B 细胞模型中高 UGT2B17 导致对氟达拉滨、伊布替尼和idelalisib 的敏感性降低。白血病细胞中 UGT2B17 的表达涉及非典型启动子，并且这些抗白血病药物短期治疗可诱导其表达。在接受相应治疗的 CLL 患者中检测到氟达拉滨和伊布替尼的葡萄糖醛酸苷，但 UGT2B17 仅结合氟达拉滨，而不结合伊布替尼。在接受氟达拉滨治疗的患者和药物处理的细胞模型中，AMP 激活的蛋白激酶作为与 UGT2B17 高表达相关的途径出现。与 UGT2B17 相关的表达变化揭示了核因子 kappa B 作为关键调节枢纽。
数据表明，UGT2B17 通过直接失活代表了改变 CLL 药物反应的机制，但对于 UGT2B17 未失活的药物，还涉及其他机制。
