http://purl.uniprot.org/citations/33419778 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/33419778 | http://www.w3.org/2000/01/rdf-schema#comment | "PurposeOn the basis of the recent discovery of mutations in Bruton tyrosine kinase (BTK) in follicular lymphoma, we studied their functional properties.Experimental designWe 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.ResultsWe 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.ConclusionsAltogether, 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."xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.org/dc/terms/identifier | "doi:10.1158/1078-0432.ccr-20-3741"xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/author | "Sun T."xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/author | "Wang S."xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/author | "Zhang J."xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/author | "Wang F."xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/author | "Xu Z."xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/author | "Xu S."xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/author | "Hu N."xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/author | "Bernard D."xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/author | "Malek S.N."xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/author | "Phillips T."xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/author | "Kaminski M."xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/author | "Devata S."xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/date | "2021"xsd:gYear |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/name | "Clin Cancer Res"xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/pages | "2301-2313"xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/title | "Follicular Lymphoma-associated BTK Mutations are Inactivating Resulting in Augmented AKT Activation."xsd:string |
http://purl.uniprot.org/citations/33419778 | http://purl.uniprot.org/core/volume | "27"xsd:string |
http://purl.uniprot.org/citations/33419778 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/33419778 |
http://purl.uniprot.org/citations/33419778 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/33419778 |
http://purl.uniprot.org/uniprot/#_B3KVH4-mappedCitation-33419778 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/33419778 |
http://purl.uniprot.org/uniprot/#_A0A0S2Z3D6-mappedCitation-33419778 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/33419778 |
http://purl.uniprot.org/uniprot/#_A0A142IKA9-mappedCitation-33419778 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/33419778 |