RRC ID |
67556
|
著者 |
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.
|
タイトル |
Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation.
|
ジャーナル |
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.
|
巻・号 |
126(1)
|
ページ |
61-8
|
公開日 |
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
|
リソース情報 |
ヒト・動物細胞 |
DT40(RCB1464) |