UGT2B17 modifies drug response in chronic lymphocytic leukaemia

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

The Expression Profiles and Deregulation of UDP-Glycosyltransferase (UGT) Genes in Human Cancers and Their Association with Clinical Outcomes

“…Moreover, our observed associations of intratumoral UGT expression with patient survival highlight their potential as prognostic biomarkers. In addition to the data shown here that assessed OS within 33 TCGA cancer types, other studies have reported the prognostic value of various UGTs in specific subsets of cancer patients [6,38,39,75]. For example, previous work shows that UGT2B17 and UGT2B28 are overexpressed in advanced and metastatic prostate cancer and associate with poor outcomes [6,[81][82][83].…”

“…The expression and activity of UGT genes within the tumor may also impact cancer development and progression through intratumoral inactivation of carcinogens and anticancer drugs. For example, high UGT2B17 expression has recently been shown to be associated with poor prognosis in chronic lymphocytic leukaemia (CLL), partly due to enhanced local inactivation of anti-leukaemic drugs (e.g., fludarabine) within CLL cells [38,39]. Therefore, it is necessary to systematically assess whether the intratumoral expression of UGT genes could be associated with clinical outcomes in different human cancers.…”

The Glycosyltransferase Pathway: An Integrated Analysis of the Cell Metabolome

“…In addition, several specific UGTs emerge as prognostic markers in multiple cancer types (leukemia, lung, prostate, colon, breast, bladder, etc.) and as predictive markers of drug responses, including in treatment-naïve patients [ 3 , 14 , 21 , 25 , 28 , 29 , 30 , 31 , 32 ]. However, the impact of UGT enzymes and alt.…”

Sex as decisive variable in lymphoid neoplasms—an update

“… 7 All UGTs are known for their high interindividual variation based on copy number variations, polymorphisms, and drug-induced expression, and, in addition, seem to be governed by alternative and/or additional forms of regulation. 99 Recently, it was shown that several of these enzymes were induced upon drug incubation of CLL cells in vitro leading to increased glucuronidation and inactivation of drugs, which included both chemotherapeutic and targeting agents. 99 The clinical consequences still have to be studied.…”

“… 99 Recently, it was shown that several of these enzymes were induced upon drug incubation of CLL cells in vitro leading to increased glucuronidation and inactivation of drugs, which included both chemotherapeutic and targeting agents. 99 The clinical consequences still have to be studied.…”