UGT2B17 modifies drug response in chronic lymphocytic leukaemia.
Adenine
/ adverse effects
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
B-Lymphocytes
/ drug effects
Biomarkers, Pharmacological
/ metabolism
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Glucuronosyltransferase
/ genetics
Humans
Leukemia, Lymphocytic, Chronic, B-Cell
/ blood
Male
Mass Spectrometry
Middle Aged
Minor Histocompatibility Antigens
/ genetics
NF-kappa B
/ genetics
Piperidines
/ adverse effects
Purines
/ adverse effects
Quinazolinones
/ adverse effects
Vidarabine
/ adverse effects
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
08
08
2019
accepted:
23
04
2020
revised:
02
04
2020
pubmed:
19
5
2020
medline:
20
2
2021
entrez:
19
5
2020
Statut:
ppublish
Résumé
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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32418995
doi: 10.1038/s41416-020-0887-6
pii: 10.1038/s41416-020-0887-6
pmc: PMC7374097
doi:
Substances chimiques
Biomarkers, Pharmacological
0
Minor Histocompatibility Antigens
0
NF-kappa B
0
Piperidines
0
Purines
0
Quinazolinones
0
ibrutinib
1X70OSD4VX
Glucuronosyltransferase
EC 2.4.1.17
UGT2B17 protein, human
EC 2.4.1.17
Vidarabine
FA2DM6879K
Adenine
JAC85A2161
fludarabine
P2K93U8740
idelalisib
YG57I8T5M0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
240-251Subventions
Organisme : Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
ID : FRN-152986
Organisme : Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
ID : FRN-408093
Commentaires et corrections
Type : CommentIn
Type : CommentIn
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