Overexpression of uridine diphospho glucuronosyltransferase 2B17 in high-risk chronic lymphocytic leukemia

Abstract

Key Points• Uridine diphospho glucuronosyltransferase 2B17 (UGT2B17) is overexpressed in poor prognostic chronic lymphocytic leukemia.Uridine diphospho glucuronosyltransferase 2B17 (UGT2B17) glucuronidates androgens and xenobiotics including certain drugs. The UGT2B17 gene shows a remarkable copy number variation (CNV), which predisposes for solid tumors and influences drug response. Here, we identify a yet undescribed UGT2B17 mRNA overexpression in poor-risk chronic lymphocytic leukemia (CLL). In total, 320 CLL patients and 449 healthy donors were analyzed. High (above median) UGT2B17 expression was associated with established CLL poor prognostic factors and resulted in shorter treatment-free and overall survival (hazard ratio ([death] 2.18; 95% CI 1.18-4.01; P ‫؍‬ .013). The prognostic impact of mRNA expression was more significant than that of UGT2B17 CNV. UGT2B17 mRNA levels in primary CLL samples directly correlated with functional glucuronidation activity toward androgens and the anticancer drug vorinostat (R > 0.9, P < .001). After treatment with fludarabine containing regimens UGT2B17 was up-regulated particularly in poor responders (P ‫؍‬ .030). We observed an exclusive involvement of the 2B17 isoform within the UGT protein family. Gene expression profiling of a stable UGT2B17 knockdown in the CLL cell line MEC-1 demonstrated a significant involvement in key cellular processes. These findings establish a relevant role of UGT2B17 in CLL with functional consequences and potential therapeutic implications. (Blood. 2013;121(7):1175-1183) IntroductionChronic lymphocytic leukemia (CLL) is characterized by a considerable heterogeneity regarding clinical presentation, need for treatment, and outcome. Many prognostic markers have been identified. 1 Although most of them provide information about risk of progression and survival, the functional role of these markers is often unclear and therapeutic consequences are therefore lacking. Apart from the clinical Rai and Binet staging systems and cytogenetics, 2-4 molecular markers, such as immunoglobulin heavy chain variable (IGHV) gene mutational status 5,6 and lipoprotein lipase (LPL) mRNA expression have strong prognostic value. 7,8 In a pilot gene expression study with 20 CLL patients, we identified a significant association of uridine diphospho (UDP) glucuronosyltransferase 2B17 (UGT2B17) with these prognostic factors. 9 Metabolizing phase 2 enzymes of the UGT2B super-family conjugate various endogenous compounds, in particular steroid hormones as well as several pharmaceutical drugs. 10,11 The UGT2B genes and pseudogenes are clustered on chromosome 4q13 and display up to 95% sequence homology among each other, which is reflected in some overlap in substrate specificity but often distinct expression profile. Isoform UGT2B17 is a major androgen inactivating enzyme playing a role in local tissuespecific regulation of it is substrates. 12 Importantly, antileukemic drugs, such as anthraquinones or the histone deacetylase (HDAC) inhibitor vorinostat, are also subject ...

Sex-dependent association of circulating sex steroids and pituitary hormones with treatment-free survival in chronic lymphocytic leukemia patients

“…Total RNA was analyzed for UGT2B17 expression using described primers and conditions [18]. Expression values were normalized to the housekeeping control genes Hprt1 and TBP which had been selected according to the qbase procedure [28].…”

Quantitative Profiling of Human Renal UDP-glucuronosyltransferases and Glucuronidation Activity: A Comparison of Normal and Tumoral Kidney Tissues

“…(Menard et al, 2013). However, some UGTs (UGT1A, UGT2B7, UGT2B15, and UGT2B17) are increased in other types of cancers, including those from the endometrium and in patients with acute myeloid leukemia and chronic lymphocytic leukemia, and emerge as a feature associated with drug resistance (Lepine et al, 2010;Dellinger et al, 2012;Gruber et al, 2013;Zahreddine et al, 2014), supporting the relevance to develop analytical tools that accurately establish the glucuronidation activity of various tissues. Although our absolute quantification of UGT proteins was conducted in kidney homogenates, they are well in line with previous reports that assessed UGT concentrations in normal kidney microsomes (Harbourt et al, 2012;Fallon et al, 2013a;Sato et al, 2014).…”

UGT2B17 expression: a novel prognostic marker within IGHV-mutated chronic lymphocytic leukemia?

“…By catalyzing the transfer of glucuronic acid from uridine diphosphoglucuronic acid to a variety of substrates, UGT2B17 detoxifies endogenous and exogenous steroid hormones and xenobiotics. 1,11,12 In this study, we analyzed the expression of UGT2B17 in 253 diagnosed CLL patients from a Scandinavian population-based CLL cohort ( (Table 1A). Thus, while confirming the results reported by Gruber et al, i.e.…”