| Autor: |
Sami N. Malek, Tycel Phillips, Suma Devata, Mark Kaminski, Shaomeng Wang, Shilin Xu, Denzil Bernard, Jing Zhang, Zhengfan Xu, Tianyu Sun, Fangyang Wang, Nan Hu |
| Rok vydání: |
2023 |
| DOI: |
10.1158/1078-0432.c.6531216.v1 |
| Popis: |
Purpose:On the basis of the recent discovery of mutations in Bruton tyrosine kinase (BTK) in follicular lymphoma, we studied their functional properties.Experimental Design:We identified novel somatic BTK mutations in 7% of a combined total of 139 follicular lymphoma and 11 transformed follicular lymphoma cases, none of which had received prior treatment with B-cell receptor (BCR) targeted drugs. We reconstituted wild-type (WT) and mutant BTK into various engineered lymphoma cell lines. We measured BCR-induced signal transduction events in engineered cell lines and primary human follicular lymphoma B cells.Results:We uncovered that all BTK mutants destabilized the BTK protein and some created BTK kinase-dead mutants. The phospholipase C gamma 2 (PLCγ2) is a substrate of BTK but the BTK mutants did not alter PLCγ2 phosphorylation. Instead, we discovered that BTK mutants induced an exaggerated AKT phosphorylation phenotype in anti-Ig-treated recombinant lymphoma cell lines. The short hairpin RNA–mediated knockdown of BTK expression in primary human nonmalignant lymph node–derived B cells resulted in strong anti-Ig-induced AKT activation, as did the degradation of BTK protein in cell lines using ibrutinib-based proteolysis targeting chimera. Finally, through analyses of primary human follicular lymphoma B cells carrying WT or mutant BTK, we detected elevated AKT phosphorylation following surface Ig crosslinking in all follicular lymphoma B cells, including all BTK-mutant follicular lymphoma. The augmented AKT phosphorylation following BCR crosslinking could be abrogated by pretreatment with a PI3Kδ inhibitor.Conclusions:Altogether, our data uncover novel unexpected properties of follicular lymphoma–associated BTK mutations with direct implications for targeted therapy development in follicular lymphoma.See related commentary by Afaghani and Taylor, p. 2123 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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