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Ref Type Journal Article
PMID (33419778)
Authors Hu N, Wang F, Sun T, Xu Z, Zhang J, Bernard D, Xu S, Wang S, Kaminski M, Devata S, Phillips T, Malek SN
Title Follicular Lymphoma-associated BTK Mutations are Inactivating Resulting in Augmented AKT Activation.
Journal Vol Issue Date Pages Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research 27 8 2021 Apr 15 2301-2313 Clin Cancer Res
URL
Abstract Text On the basis of the recent discovery of mutations in Bruton tyrosine kinase ( BTK ) in follicular lymphoma, we studied their functional properties. 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. 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. 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 .

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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
BTK E90K missense unknown BTK E90K lies within the PH domain of the Btk protein (UniProt.org). E90K retains binding to Plcg2 and Cdc37, and demonstrates Plcg2 phosphorylation and Btk autophosphorylation levels similar to wild-type Btk, but results in decreased protein stability and expression, and elevated phosphorylation of Akt in anti-immunoglobulin treated cells in culture (PMID: 33419778), and therefore, its effect on Btk protein function is unknown.
BTK K433T missense loss of function BTK K433T lies within the protein kinase domain of the Btk protein (UniProt.org). K433T retains binding to Plcg2 and Cdc37, but results in decreased protein stability and expression, loss of Plcg2 phosphorylation and Btk autophosphorylation, and elevated phosphorylation of Akt in anti-immunoglobulin treated patient cells in culture (PMID: 33419778).
BTK P566L missense loss of function BTK P566L lies within the protein kinase domain of the Btk protein (UniProt.org). P566L retains binding to Plcg2 and Cdc37, but results in decreased protein stability and expression, loss of Plcg2 phosphorylation and Btk autophosphorylation, and elevated phosphorylation of Akt in anti-immunoglobulin treated cells in culture (PMID: 33419778).
BTK P597S missense loss of function BTK P597S lies within the protein kinase domain of the Btk protein (UniProt.org). P597S retains binding to Plcg2 and Cdc37, but results in decreased protein stability and expression, loss of Plcg2 phosphorylation and Btk autophosphorylation, leads to elevated phosphorylation of Akt in anti-immunoglobulin treated cells in culture (PMID: 33419778).
BTK R77S missense unknown BTK R77S lies within the PH domain of the Btk protein (UniProt.org). R77S retains binding to Plcg2 and Cdc37, and demonstrates Plcg2 phosphorylation and Btk autophosphorylation levels similar to wild-type Btk, but results in decreased protein stability and expression, and elevated phosphorylation of Akt in anti-immunoglobulin treated cells in culture (PMID: 33419778), and therefore, its effect on Btk protein function is unknown.
BTK V568I missense loss of function BTK V568I lies within the protein kinase domain of the Btk protein (UniProt.org). V568I retains binding to Plcg2 and Cdc37, but results in decreased protein stability and expression, loss of Plcg2 phosphorylation and Btk autophosphorylation, and leads to elevated phosphorylation of Akt in anti-immunoglobulin treated cells in culture (PMID: 33419778).
BTK Y315N missense unknown BTK Y315N lies within the SH2 domain of the Btk protein (UniProt.org). Y315N retains binding to Plcg2 and Cdc37 and demonstrates Plcg2 phosphorylation and Btk autophosphorylation levels similar to wild-type Btk, but results in decreased protein stability and expression, elevated phosphorylation of Akt in anti-immunoglobulin treated cells, and is associated with resistance to Btk inhibition in culture (PMID: 33419778), and therefore, its effect on Btk protein function is unknown. Y
BTK Y361H missense unknown BTK Y361H lies within the SH2 domain of the Btk protein (UniProt.org). Y361H retains binding to Plcg2 and Cdc37, and demonstrates Plcg2 phosphorylation and Btk autophosphorylation levels similar to wild-type Btk, but results in decreased protein stability and expression, and elevated phosphorylation of Akt in anti-immunoglobulin treated cells in culture (PMID: 33419778), and therefore, its effect on Btk protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BTK K433T lymphoma sensitive Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, a lymphoma cell line expressing BTK K433T was sensitive to Imbruvica (ibrutinib) treatment in culture, demonstrating decreased cell viability (PMID: 33419778). 33419778
BTK P566L lymphoma sensitive Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, lymphoma cell lines expressing BTK P566L were sensitive to Imbruvica (ibrutinib) treatment in culture, demonstrating decreased cell viability (PMID: 33419778). 33419778
BTK E90K lymphoma sensitive Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, lymphoma cell lines expressing BTK E90K were sensitive to Imbruvica (ibrutinib) treatment in culture, demonstrating decreased cell viability (PMID: 33419778). 33419778
BTK Y361H lymphoma sensitive Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, a lymphoma cell line expressing BTK Y361H was sensitive to Imbruvica (ibrutinib) treatment in culture, demonstrating decreased cell viability (PMID: 33419778). 33419778
BTK Y315N lymphoma resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, lymphoma cell lines expressing BTK Y315N were resistant to treatment with Imbruvica (ibrutinib) in culture (PMID: 33419778). 33419778
BTK V568I lymphoma sensitive Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, lymphoma cell lines expressing BTK V568I were sensitive to Imbruvica (ibrutinib) treatment in culture, demonstrating decreased cell viability (PMID: 33419778). 33419778
BTK P597S lymphoma resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, lymphoma cell lines expressing BTK P597S were resistant to treatment with Imbruvica (ibrutinib) in culture (PMID: 33419778). 33419778
BTK R77S lymphoma sensitive Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, lymphoma cell lines expressing BTK R77S were sensitive to Imbruvica (ibrutinib) treatment in culture, demonstrating decreased cell viability (PMID: 33419778). 33419778