Follicular Lymphoma-associated BTK Mutations are Inactivating Resulting in Augmented AKT Activation.
Agammaglobulinaemia Tyrosine Kinase
/ genetics
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases
/ antagonists & inhibitors
DNA Mutational Analysis
Gene Knockdown Techniques
HEK293 Cells
Humans
Loss of Function Mutation
Lymphoma, Follicular
/ genetics
Mutagenesis, Site-Directed
Phospholipase C gamma
/ metabolism
Phosphorylation
/ drug effects
Primary Cell Culture
Protein Stability
Proto-Oncogene Proteins c-akt
/ metabolism
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 04 2021
15 04 2021
Historique:
received:
21
09
2020
revised:
29
09
2020
accepted:
05
01
2021
pubmed:
10
1
2021
medline:
15
3
2022
entrez:
9
1
2021
Statut:
ppublish
Résumé
On the basis of the recent discovery of mutations in Bruton tyrosine kinase ( We identified novel somatic 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 Altogether, our data uncover novel unexpected properties of follicular lymphoma-associated BTK mutations with direct implications for targeted therapy development in follicular lymphoma.
Identifiants
pubmed: 33419778
pii: 1078-0432.CCR-20-3741
doi: 10.1158/1078-0432.CCR-20-3741
pmc: PMC8046715
mid: NIHMS1662274
doi:
Substances chimiques
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CA protein, human
EC 2.7.1.137
Agammaglobulinaemia Tyrosine Kinase
EC 2.7.10.2
BTK protein, human
EC 2.7.10.2
AKT1 protein, human
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
PLCG2 protein, human
EC 3.1.4.3
Phospholipase C gamma
EC 3.1.4.3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2301-2313Subventions
Organisme : NCI NIH HHS
ID : R01 CA190384
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2021 American Association for Cancer Research.
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