Allain Eric P, Rouleau Michèle, Le Trang, Vanura Katrina, Villeneuve Lyne, Caron Patrick, Turcotte Véronique, Lévesque Eric, Guillemette Chantal
Pharmacogenomics Laboratory, Faculty of Pharmacy, Centre Hospitalier Universitaire de Québec (CHU de Québec) Research Center - Université Laval, Laval University, Québec City, QC, Canada.
Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
Front Oncol. 2019 Jul 4;9:606. doi: 10.3389/fonc.2019.00606. eCollection 2019.
High expression of the metabolic enzyme UDP-glucuronosyltransferase UGT2B17 in chronic lymphocytic leukemia (CLL) cells was associated with poor prognosis in two independent studies. However, the underlying mechanism remains unknown. We hypothesized that UGT2B17 impacts intracellular levels of hormone-like signaling molecules involved in the regulation of gene expression in leukemic cells. We initially confirmed in a third cohort of 291 CLL patients that those with high UGT2B17 displayed poor prognosis (hazard ratio of 2.31, = 0.015). Consistent with the unfavorable prognostic significance of elevated UGT2B17 expression in CLL patients, high UGT2B17 expression was associated with enhanced proliferation of MEC1 and JVM2 malignant B-cell models. Transcriptomic analyses revealed that high UGT2B17 was linked to a significant alteration of genes related to prostaglandin E2 (PGE) and to its precursor arachidonic acid, both in cell models and a cohort of 448 CLL patients. In functional assays, PGE emerged as a negative regulator of apoptosis in CLL patients and proliferation in cells models, whereas its effect was partially abrogated by high UGT2B17 expression in MEC1 and JVM2 cells. Enzymatic assays and mass-spectrometry analyses established that the UGT2B17 enzyme inactivates PGE by its conjugation to glucuronic acid (GlcA) leading to the formation of two glucuronide (G) derivatives. High UGT2B17 expression was further associated with a proficient inactivation of PGE to PGE-G in CLL patient cells and cell models. We conclude that UGT2B17-dependent PGE glucuronidation impairs anti-oncogenic PGE effects in leukemic cells, thereby partially contributing to disease progression in high UGT2B17 CLL patients.
在两项独立研究中，代谢酶尿苷二磷酸葡萄糖醛酸基转移酶UGT2B17在慢性淋巴细胞白血病（CLL）细胞中的高表达与预后不良相关。然而，其潜在机制仍不清楚。我们推测UGT2B17会影响白血病细胞中参与基因表达调控的激素样信号分子的细胞内水平。我们最初在由291名CLL患者组成的第三队列中证实，UGT2B17水平高的患者预后较差（风险比为2.31，P = 0.015）。与CLL患者中UGT2B17表达升高的不良预后意义一致，UGT2B17高表达与MEC1和JVM2恶性B细胞模型的增殖增强相关。转录组分析显示，在细胞模型和448名CLL患者队列中，UGT2B17高表达均与前列腺素E2（PGE）及其前体花生四烯酸相关基因的显著改变有关。在功能试验中，PGE是CLL患者细胞凋亡和细胞模型增殖的负调节因子，而在MEC1和JVM2细胞中，其作用因UGT2B17高表达而部分被消除。酶活性测定和质谱分析证实，UGT2B17酶通过将PGE与葡萄糖醛酸（GlcA）结合使其失活，导致形成两种葡萄糖醛酸苷（G）衍生物。UGT2B17高表达还与CLL患者细胞和细胞模型中PGE高效失活为PGE-G相关。我们得出结论，UGT2B17依赖的PGE葡萄糖醛酸化损害了白血病细胞中PGE的抗癌作用，从而部分导致了UGT2B17高表达的CLL患者的疾病进展。
