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

Bhoi, Sujata; Baliakas, Panagiotis; Cortese, Diego; Mattsson, Mattias; Engvall, Marie; Smedby, Karin E.; Juliusson, Gunnar; Sutton, Lesley-Ann; Mansouri, Larry

doi:10.3324/haematol.2015.136440

Cited by 18 publications

(35 citation statements)

References 12 publications

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“…The specificity of the EL-2B17mAb monoclonal antibody produced in this study is an important additional molecular tool capable of specifically detecting the UGT2B17 protein both in WB and IHC and could expedite clinical advances on the significance of UGT2B17 in drug metabolism (Turgeon et al, 2003;Kang et al, 2010;Sun et al, 2010;Taghavi et al, 2017;Kahma et al, 2018) and cancer biology (Nadeau et al, 2011;Gruber et al, 2013;Bhoi et al, 2016;Li et al, 2016). It is the first antibody with a unique specificity for UGT2B17 without any cross-reactivity to any other human UGT2B enzymes, including the highly similar UGT2B15.…”

Section: Discussionmentioning

confidence: 97%

“…Besides additional genetic variants in the UGT2B17 gene locus, those affecting expression of the FOXA1 transcription factor might also be important. This knowledge will help understand the biologic impact of this enzyme in health and diseases, namely, on the endocrine system (Juul et al, 2009;Mouritsen et al, 2018), osteoporosis (Yang et al, 2008), carcinogen exposure (Chen et al, 2010), head and neck cancer (Mafune et al, 2015), prostate cancer (Kpoghomou et al, 2013;Li et al, 2016), chronic lymphocytic leukemia (Gruber et al, 2013;Bhoi et al, 2016), pediatric cancer (Ishimaru et al, 2017), and on inactivation of antineoplastic and other therapeutic agents (Kang et al, 2010;Sun et al, 2010;Wang et al, 2012).…”

Section: Specific Quantification Of Ugt2b17mentioning

confidence: 99%

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Factors Affecting Interindividual Variability of Hepatic UGT2B17 Protein Expression Examined Using a Novel Specific Monoclonal Antibody

et al. 2019

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Accurate quantification of the metabolic enzyme uridine diphosphoglucuronosyltransferase (UGT) UGT2B17 has been hampered by the high sequence identity with other UGT2B enzymes (as high as 94%) and by the lack of a specific antibody. Knowing the significance of the UGT2B17 pathway in drug and hormone metabolism and cancer, we developed a specific monoclonal antibody (EL-2B17mAb), initially validated by the lack of detection in liver microsomes of an individual carrying no UGT2B17 gene copy and in supersomes expressing UGT2B enzymes. Immunohistochemical detection in livers revealed strong labeling of bile ducts and variable labeling of hepatocytes. Expression levels assessed by immunoblotting were highly correlated to mass spectrometry-based quantification (r = 0.93), and three major expression patterns (absent, low, or high) were evidenced. Livers with very low expression were carriers of the functional rs59678213 G variant, located in the binding site for the transcription factor forkhead box A1 (FOXA1) of the UGT2B17 promoter. The highest level of expression was observed for individuals carrying at least one rs59678213 A allele. Multiple regression analysis indicated that the number of gene copies explained only 8% of UGT2B17 protein expression, 49% when adding rs59678213, reaching 54% when including sex. The novel EL-2B17mAb antibody allowed specific UGT2B17 quantification and exposed different patterns of hepatic expression. It further suggests that FOXA1 is a key driver of UGT2B17 expression in the liver. The availability of this molecular tool will help characterize the UGT2B17 level in various disease states and establish more precisely the contribution of the UGT2B17 enzyme to drug and hormone metabolism.

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Section: Discussionmentioning

confidence: 97%

Section: Specific Quantification Of Ugt2b17mentioning

confidence: 99%

Factors Affecting Interindividual Variability of Hepatic UGT2B17 Protein Expression Examined Using a Novel Specific Monoclonal Antibody

et al. 2019

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“…For example, the UGT2B17 gene deletion (homozygous) is associated with decreases in fat mass (P , 0.01) and insulin sensitivity (P , 0.05) (Swanson et al, 2007), and the males with lower testosterone levels are 2.4 times more likely to be obese than males with higher testosterone levels (Mulligan et al, 2006). On the other hand, high UGT2B17 protein levels have been identified as the strongest independent molecular prognostic marker of overall survival in mutated chronic lymphocytic leukemia patients (Bhoi et al, 2016). The UGT2B17 deletion (homozygous) genotype is associated with a decreased risk of colorectal cancer in men, but it was nonpredictive in women (Angstadt et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Hepatic Abundance and Activity of Androgen- and Drug-Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, and Sex

et al. 2018

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The major objective of this study was to investigate the association of genetic and nongenetic factors with variability in protein abundance and in vitro activity of the androgen-metabolizing enzyme UGT2B17 in human liver microsomes ( = 455). UGT2B17 abundance was quantified by liquid chromatography-tandem mass spectrometry proteomics, and enzyme activity was determined by using testosterone and dihydrotestosterone as in vitro probe substrates. Genotyping or gene resequencing and mRNA expression were also evaluated. Multivariate analysis was used to test the association of UGT2B17 copy number variation, single nucleotide polymorphisms (SNPs), age, and sex with its mRNA expression, abundance, and activity. UGT2B17 gene copy number and SNPs (rs7436962, rs9996186, rs28374627, and rs4860305) were associated with gene expression, protein levels, and androgen glucuronidation rates in a gene dose-dependent manner. UGT2B17 protein (mean ± S.D. picomoles per milligram of microsomal protein) is sparsely expressed in children younger than 9 years (0.12 ± 0.24 years) but profoundly increases from age 9 years to adults (∼10-fold) with ∼2.6-fold greater abundance in males than in females (1.2 vs. 0.47). Association of androgen glucuronidation with UGT2B15 abundance was observed only in the low UGT2B17 expressers. These data can be used to predict variability in the metabolism of UGT2B17 substrates. Drug companies should include UGT2B17 in early phenotyping assays during drug discovery to avoid late clinical failures.

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“…50 A second report validated UGT2B17 as an informative prognostic marker in a Scandinavian cohort of 253 CLL patients and also among CLL patients with a mutated immunoglobulin heavy-chain variable region gene, a group for which few prognostic indicators exist. 57 These studies imply a relevant role of the UGT2B17 pathway in progressive CLL and provide novel prognostic information. Based on enzymatic assays performed on patient samples, transcriptional expression correlates with UGT2B17 catalytic activity, implying a possible link between poor CLL survival and enhanced UGT2B17 conjugation activity.…”

Section: Ugt2b17mentioning

confidence: 91%

“…17,29,31,33,50,[53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69] The expression of UGTs is repressed in certain tumour types relative to their normal tissue counterparts, but remarkably enhanced in other cancers, such as those of the prostate, pancreas, lung, endometrium and in CLL, indicating diverse patterns of regulation of UGT expression in tumours. 17,29,31,33,50,[53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69] These perturbed levels of UGTs are consistent with altered metabolic functions in tumours and suggest that UGTs might influence cancer progression, independent of exposure to therapeutic drugs (Table 1). Notably, in recent reports investigating metabolic perturbations present in the transcriptome and metabolome of multiple tumour types, 7...…”

Section: Ugts and Cancer Progressionmentioning

confidence: 99%

Emerging roles for UDP-glucuronosyltransferases in drug resistance and cancer progression

et al. 2020

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The best-known role of UDP-glucuronosyltransferase enzymes (UGTs) in cancer is the metabolic inactivation of drug therapies. By conjugating glucuronic acid to lipophilic drugs, UGTs impair the biological activity and enhance the water solubility of these agents, driving their elimination. Multiple clinical observations support an expanding role for UGTs as modulators of the drug response and in mediating drug resistance in numerous cancer types. However, accumulating evidence also suggests an influence of the UGT pathway on cancer progression. Dysregulation of the expression and activity of UGTs has been associated with the progression of several cancers, arguing for UGTs as possible mediators of oncogenic pathways and/or disease accelerators in a drug-naive context. The consequences of altered UGT activity on tumour biology are incompletely understood. They might be associated with perturbed levels of bioactive endogenous metabolites such as steroids and bioactive lipids that are inactivated by UGTs or through non-enzymatic mechanisms, thereby eliciting oncogenic signalling cascades. This review highlights the evidence supporting dual roles for the UGT pathway, affecting cancer progression and drug resistance. Pharmacogenomic testing of UGT profiles in patients and the development of therapeutic options that impair UGT actions could provide useful prognostic and predictive biomarkers and enhance the efficacy of anti-cancer drugs.

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

Cited by 18 publications

References 12 publications

Factors Affecting Interindividual Variability of Hepatic UGT2B17 Protein Expression Examined Using a Novel Specific Monoclonal Antibody

Factors Affecting Interindividual Variability of Hepatic UGT2B17 Protein Expression Examined Using a Novel Specific Monoclonal Antibody

Hepatic Abundance and Activity of Androgen- and Drug-Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, and Sex

Emerging roles for UDP-glucuronosyltransferases in drug resistance and cancer progression

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