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

In chronic lymphocytic leukemia (CLL), an elevated glycosyltransferase UGT2B17 expression (UGT2B17HI) 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 UGT2B17HI 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.

 

Comments:

The information highlights the discovery of a potential mechanism involving UGT2B17 in chronic lymphocytic leukemia (CLL). This mechanism appears to be independent of UGT2B17's enzymatic function and is associated with poor drug response and shorter survival in CLL patients.

The study revealed that CLL patients with elevated UGT2B17 expression (UGT2B17HI) exhibited enhanced expression and signaling of pro-survival B cell receptor (BCR) pathway effectors, as well as increased phosphorylation of Bruton tyrosine kinase (BTK) in B-CLL cells. Additionally, UGT2B17 expression was strongly correlated with the adverse marker ZAP70, which encodes a tyrosine kinase promoting B-CLL cell survival. When UGT2B17 expression and ZAP70 levels were combined, they defined a prognostic group with the highest risk of poor survival among treatment-naïve patients.

Further investigation demonstrated that UGT2B17 may interact with several kinases of the BCR pathway, including ZAP70, SYK, and BTK, suggesting a potential role for UGT2B17 in this signaling cascade. The study also found that UGT2B17 knockout and repression of ZAP70 in leukemic cells led to reduced proliferation, supporting the involvement of UGT2B17 in promoting CLL cell growth.

From a therapeutic perspective, the dual SYK and JAK/STAT6 inhibitor cerdulatinib was found to effectively disrupt the proliferative advantage conferred by UGT2B17, compared to the selective BTK inhibitor ibrutinib. This finding suggests a potential therapeutic vulnerability associated with the UGT2B17-driven pathway.

In summary, the study provides evidence of an oncogenic role for UGT2B17 in CLL, revealing its involvement as a novel constituent of the BCR signalosome. The findings also suggest a connection between UGT2B17 and microenvironmental signaling in CLL. Further research and clinical studies are warranted to validate these findings and explore the potential of targeting UGT2B17 and its associated pathways for improved CLL treatment.

Related Products

Cat.No. Product Name Information
S7634 Cerdulatinib (PRT062070) hydrochloride Cerdulatinib (PRT-062070, PRT2070) hydrochloride is an oral active, multi-targeted tyrosine kinase inhibitor with IC50 of 12 nM/6 nM/8 nM/0.5 nM and 32 nM for JAK1/JAK2/JAK3/TYK2 and Syk, respectively. Also inhibits 19 other tested kinases with IC50 less than 200 nM.

Related Targets

Syk JAK