Noncatalytic Bruton's tyrosine kinase activates PLCγ₂ variants mediating ibrutinib resistance in human chronic lymphocytic leukemia cells.

ABSTRACT: Treatment of patients with chronic lymphocytic leukemia (CLL) with inhibitors of Bruton's tyrosine kinase (BTK), such as ibrutinib, is limited by primary or secondary resistance to this drug. Examinations of CLL patients with late relapses while on ibrutinib, which inhibits BTK's catalytic activity, revealed several mutations in BTK, most frequently resulting in the C481S substitution, and disclosed many mutations in PLCG2, encoding phospholipase C-γ₂ (PLCγ₂). The PLCγ₂ variants typically do not exhibit constitutive activity in cell-free systems, leading to the suggestion that in intact cells they are hypersensitive to Rac family small GTPases or to the upstream kinases spleen-associated tyrosine kinase (SYK) and Lc

SUBMITTER: Wist M 

PROVIDER: S-EPMC7186163 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature