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|Ref Type||Journal Article|
|Authors||Malek S, Hu N, Wang F, Sun T, Xu Z, Zhang J, Bernard D, Xu S, Wang S, Kaminski MS, Devata S, Phillips T|
|Title||Follicular lymphoma-associated BTK mutations are inactivating resulting in augmented AKT activation.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2021 Jan 08|
|Abstract Text||Based on the recent discovery of mutations in Bruton's tyrosine kinase (BTK) in Follicular Lymphoma (FL), we studied their functional properties.We identified novel somatic BTK mutations in 7% of a combined total of 139 FL and 11 transformed FL cases, none of which had received prior treatment with B cell receptor (BCR) targeted drugs. We reconstituted WT and mutant BTK into various engineered lymphoma cell lines. We measured BCR-induced signal transduction events in engineered cell lines and primary human FL B cells.We uncovered that all BTK mutants destabilized the BTK protein and some created BTK kinase-dead mutants. The 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-immunoglobulin (IG) treated recombinant lymphoma cell lines. The shRNA-mediated knock-down of BTK expression in primary human non-malignant lymph node-derived B cells resulted in strong anti-IG-induced AKT activation, as did the degradation of BTK protein in cells lines using ibrutinib-based proteolysis targeting chimera (PROTAC). Finally, through analyses of primary human FL B cells carrying WT or mutant BTK, we detected elevated AKT phosphorylation following surface IG crosslinking in all FL B cells, including all BTK mutant FL. The augmented AKT phosphorylation following BCR crosslinking could be abrogated by pre-treatment with a PI3Kδ inhibitor.Altogether, our data uncover novel unexpected properties of FL-associated BTK mutations with direct implications for targeted therapy development in FL.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|