The UGT1A isoforms 2 act as negative modulators of their isoform 1 homologs in microsome preparations, revealing a new regulatory mechanism of the glucuronidation pathway. Findings further provide the first direct evidence of a novel alternative splicing mechanism at the 3' end of the UGT1 locus that further increases the number of proteins derived from this single gene.

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 ...