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 PLCγ₂ an ∼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 PLCγ₂ mutants 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 "ba

SUBMITTER: Walliser C 

PROVIDER: S-EPMC5063995 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature