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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
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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	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	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.
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	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	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).

Showing 1 to 8 of 8 entries

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Showing 1 to 8 of 8 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 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 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
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 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 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

Showing 1 to 8 of 8 entries

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