hypermorph

Hypermorphic mutation of phospholipase C, gamma 2 acquired in ibrutinib resistant CLL confers BTK independency upon BCR activation.

Hypermorphic mutation of phospholipase C, gamma 2 acquired in ibrutinib resistant CLL confers BTK independency upon BCR activation.

Blood. 2015 May 13;

Authors: 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

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, gamma 2 (PLCG2). While 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.

PMID: 25972157 [PubMed - as supplied by publisher]



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