UGT2B17 modifies drug response in chronic lymphocytic leukaemia.
Eric P Allain, Michèle Rouleau, Katrina Vanura, Sophie Tremblay, Joanie Vaillancourt, Vincent Bat, Patrick Caron, Lyne Villeneuve, Adrien Labriet, Véronique Turcotte, Trang Le, Medhat Shehata, Susanne Schnabl, Dita Demirtas, Rainer Hubmann, Charles Joly-Beauparlant, Arnaud Droit, Ulrich Jäger, Philipp B Staber, Eric Lévesque, Chantal Guillemette
British journal of cancer 2020 JulHigh 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. 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. 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. 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.
Citation
Eric P Allain, Michèle Rouleau, Katrina Vanura, Sophie Tremblay, Joanie Vaillancourt, Vincent Bat, Patrick Caron, Lyne Villeneuve, Adrien Labriet, Véronique Turcotte, Trang Le, Medhat Shehata, Susanne Schnabl, Dita Demirtas, Rainer Hubmann, Charles Joly-Beauparlant, Arnaud Droit, Ulrich Jäger, Philipp B Staber, Eric Lévesque, Chantal Guillemette. UGT2B17 modifies drug response in chronic lymphocytic leukaemia. British journal of cancer. 2020 Jul;123(2):240-251
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PMID: 32418995
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