A Non-Canonical Role for the Glycosyltransferase Enzyme UGT2B17 as a Novel Constituent of the B Cell Receptor Signalosome.

Cells

Centre Hospitalier Universitaire de Québec Research Center-Université Laval (CRCHUQc-UL), Faculty of Pharmacy, and Centre de Recherche sur le Cancer de l'Université Laval (CRC-UL), Université Laval, Québec, QC G1V 4G2, Canada.

Published: May 2023

In chronic lymphocytic leukemia (CLL), an elevated glycosyltransferase UGT2B17 expression (UGT2B17) identifies a subgroup of patients with shorter survival and poor drug response. We uncovered a mechanism, possibly independent of its enzymatic function, characterized by an enhanced expression and signaling of the proximal effectors of the pro-survival B cell receptor (BCR) pathway and elevated Bruton tyrosine kinase (BTK) phosphorylation in B-CLL cells from UGT2B17 patients. A prominent feature of B-CLL cells is the strong correlation of UGT2B17 expression with the adverse marker ZAP70 encoding a tyrosine kinase that promotes B-CLL cell survival. Their combined high expression levels in the treatment of naïve patients further defined a prognostic group with the highest risk of poor survival. In leukemic cells, UGT2B17 knockout and repression of ZAP70 reduced proliferation, suggesting that the function of UGT2B17 might involve ZAP70. Mechanistically, UGT2B17 interacted with several kinases of the BCR pathway, including ZAP70, SYK, and BTK, revealing a potential therapeutic vulnerability. The dual SYK and JAK/STAT6 inhibitor cerdulatinib most effectively compromised the proliferative advantage conferred by UGT2B17 compared to the selective BTK inhibitor ibrutinib. Findings point to an oncogenic role for UGT2B17 as a novel constituent of BCR signalosome also connected with microenvironmental signaling.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10177405PMC
http://dx.doi.org/10.3390/cells12091295DOI Listing

Publication Analysis

Top Keywords

ugt2b17
10
ugt2b17 novel
8
novel constituent
8
cell receptor
8
ugt2b17 expression
8
bcr pathway
8
tyrosine kinase
8
b-cll cells
8
cells ugt2b17
8
non-canonical role
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!