RRC ID 67556
Author Liu TM, Woyach JA, Zhong Y, Lozanski A, Lozanski G, Dong S, Strattan E, Lehman A, Zhang X, Jones JA, Flynn J, Andritsos LA, Maddocks K, Jaglowski SM, Blum KA, Byrd JC, Dubovsky JA, Johnson AJ.
Title Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation.
Journal Blood
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.
Volume 126(1)
Pages 61-8
Published 2015-7-2
DOI 10.1182/blood-2015-02-626846
PII S0006-4971(20)31483-X
PMID 25972157
PMC PMC4492196
MeSH Adenine / analogs & derivatives Agammaglobulinaemia Tyrosine Kinase Animals Antineoplastic Combined Chemotherapy Protocols / pharmacology Cells, Cultured Chickens Drug Resistance, Neoplasm / drug effects Drug Resistance, Neoplasm / genetics* Humans Intracellular Signaling Peptides and Proteins / antagonists & inhibitors Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy* Leukemia, Lymphocytic, Chronic, B-Cell / genetics* Leukemia, Lymphocytic, Chronic, B-Cell / metabolism Mutation, Missense Phospholipase C gamma / genetics* Piperidines Protein-Tyrosine Kinases / antagonists & inhibitors Protein-Tyrosine Kinases / physiology* Pyrazoles / therapeutic use* Pyrimidines / therapeutic use* Receptors, Antigen, B-Cell / metabolism* Signal Transduction / genetics Syk Kinase src-Family Kinases / antagonists & inhibitors
IF 17.794
Human and Animal Cells DT40(RCB1464)