title: Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation.
abstract: Ibrutinib has significantly improved the outcome of patients with relapsed chronic lymphocytic leukemia (CLL). Recent reports attribute ibrutinib resistance to acquired mutations in Bruton agammaglobulinemia tyrosine kinase (BTK), the target of ibrutinib, as well as the immediate downstream effector phospholipase C, γ2 (PLCG2). Although the C481S mutation found in BTK has been shown to disable ibrutinib's capacity to irreversibly bind this primary target, the detailed mechanisms of mutations in PLCG2 have yet to be established. Herein, we characterize the enhanced signaling competence, BTK independence, and surface immunoglobulin dependence of the PLCG2 mutation at R665W, which has been documented in ibrutinib-resistant CLL. Our data demonstrate that this missense alteration elicits BTK-independent activation after B-cell receptor engagement, implying the formation of a novel BTK-bypass pathway. Consistent with previous results, PLCG2(R665W) confers hypermorphic induction of downstream signaling events. Our studies reveal that proximal kinases SYK and LYN are critical for the activation of mutant PLCG2 and that therapeutics targeting SYK and LYN can combat molecular resistance in cell line models and primary CLL cells from ibrutinib-resistant patients. Altogether, our results engender a molecular understanding of the identified aberration at PLCG2 and explore its functional dependency on BTK, SYK, and LYN, suggesting alternative strategies to combat acquired ibrutinib resistance.
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: Ta-Ming
authors.initials: TM
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: Arletta
authors.initials: A
authors.lastname: Lozanski
authors.affiliation: Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH; and.
authors.forename: Gerard
authors.initials: G
authors.lastname: Lozanski
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: Shuai
authors.initials: S
authors.lastname: Dong
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: Ethan
authors.initials: E
authors.lastname: Strattan
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH.
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jones
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Flynn
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Andritsos
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: Kami
authors.initials: K
authors.lastname: Maddocks
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Jaglowski
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Dubovsky
authors.affiliation: Department of Internal Medicine, Division of Hematology, and.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002478:Cells, Cultured; D002645:Chickens; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D051966:Phospholipase C gamma / Q000235:genetics*; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000606896:SYK protein, human; D000072377:Syk Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051966:Phospholipase C gamma; D000225:Adenine