Exposure to Therapeutic BTK Inhibitors Induces Phenocopying of Mutants in the Fruit Fly .

Background: Bruton's tyrosine kinase (BTK) is a non-receptor type tyrosine kinase originally identified as the genetic signature responsible for X-linked agammaglobulinemia (XLA) when mutated. Its functional form is required for B lymphocyte maturation in both humans and mice, whereas loss-of-function causes a different form of developmental defect in the fruit fly, .

Methods: Ibrutinib and other therapeutic inhibitors of BTK have been extensively used to successfully treat various leukemias and lymphomas. type 2 is the ortholog of BTK in the fruit fly. We show that feeding wild-type flies an ibrutinib-containing diet induces phenocopying of mutants, i.e., failure in the fusion of left and right halves of the dorsal cuticles, partial loss of wing tissues and dysregulation of germ cell production.

Results: We have previously reported that phosphorylates Arm (β-catenin), and ibrutinib reduces phosphorylation at Tyrosine142 of endogenously expressed β-catenin in Cos7 cells transfected with type 2 cDNA.

Conclusions: Thus, is suitable for screens of novel BTK inhibitor candidates and offers a unique system in which the mode of action of BTK inhibitors can be examined at the molecular, cellular, and organismal levels.