title: The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein.
abstract: Mutations in the gene encoding phospholipase C-γ2(PLCγ2) have been shown to be associated with resistance to targeted therapy of chronic lymphocytic leukemia (CLL) with the Bruton's tyrosine kinase inhibitor ibrutinib. The fact that two of these mutations, R665W and L845F, imparted upon PLCγ2an ∼2-3-fold ibrutinib-insensitive increase in the concentration of cytosolic Ca2+following ligation of the B cell antigen receptor (BCR) led to the assumption that the two mutants exhibit constitutively enhanced intrinsic activity. Here, we show that the two PLCγ2mutants are strikingly hypersensitive to activation by Rac2 such that even wild-type Rac2 suffices to activate the mutant enzymes upon its introduction into intact cells. Enhanced "basal" activity of PLCγ2in intact cells is shown using the pharmacologic Rac inhibitor EHT 1864 and the PLCγ2F897Qmutation mediating Rac resistance to be caused by Rac-stimulated rather than by constitutively enhanced PLCγ2activity. We suggest that R665W and L845F be referred to as allomorphic rather than hypermorphic mutations of PLCG2 Rerouting of the transmembrane signals emanating from BCR and converging on PLCγ2through Rac in ibrutinib-resistant CLL cells may provide novel drug treatment strategies to overcome ibrutinib resistance mediated by PLCG2 mutations or to prevent its development in ibrutinib-treated CLL patients.
authors.affiliation: From the Institute of Pharmacology and Toxicology and.
authors.forename: Claudia
authors.initials: C
authors.lastname: Walliser
authors.affiliation: From the Institute of Pharmacology and Toxicology and.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hermkes
authors.affiliation: From the Institute of Pharmacology and Toxicology and.
authors.forename: Anja
authors.initials: A
authors.lastname: Schade
authors.affiliation: the Core Unit Mass Spectrometry and Proteomics, Medical Faculty, Ulm University, 89081 Ulm, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wiese
authors.affiliation: From the Institute of Pharmacology and Toxicology and.
authors.forename: Julia
authors.initials: J
authors.lastname: Deinzer
authors.affiliation: the Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany, and.
authors.forename: Marc
authors.initials: M
authors.lastname: Zapatka
authors.affiliation: the Diaxonhit, 63-65 Boulevard Masséna, 75013 Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Désiré
authors.affiliation: Department of Internal Medicine III, Ulm University Medical Center, 89070 Ulm, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mertens
authors.affiliation: Department of Internal Medicine III, Ulm University Medical Center, 89070 Ulm, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: From the Institute of Pharmacology and Toxicology and peter.gierschik@uni-ulm.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Gierschik
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010880:Piperidines; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000097766:RAC2 GTP-Binding Protein
chemical_list: D000225:Adenine; D009363:Neoplasm Proteins; D051966:Phospholipase C gamma; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D011753:Pyrones; D011804:Quinolines; D011947:Receptors, Antigen, B-Cell; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein; C506907:EHT 1864; C551803:ibrutinib
keywords: Rac (Rac GTPase); chronic lymphocytic leukemia; ibrutinib resistance; leukemia; lymphoma; phosphatidylinositol signaling; phospholipase C