Frontiers in Bioscience-Landmark (Jun 2023)

Exposure to Therapeutic BTK Inhibitors Induces Phenocopying of Btk29A Mutants in the Fruit Fly Drosophila melanogaster

  • Noriko Hamada-Kawaguchi,
  • Beston F. Nore,
  • Rula Zain,
  • Ylva Engström,
  • C. I. Edvard Smith,
  • Daisuke Yamamoto

DOI
https://doi.org/10.31083/j.fbl2806124
Journal volume & issue
Vol. 28, no. 6
p. 124

Abstract

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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, Drosophila melanogaster. Methods: Ibrutinib and other therapeutic inhibitors of BTK have been extensively used to successfully treat various leukemias and lymphomas. Btk29A 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 Btk29A 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 Btk29A phosphorylates Drosophila Arm (β-catenin), and ibrutinib reduces phosphorylation at Tyrosine142 of endogenously expressed β-catenin in Cos7 cells transfected with Btk29A type 2 cDNA. Conclusions: Thus, Drosophila is suitable for screens of novel BTK inhibitor candidates and offers a unique in vivo system in which the mode of action of BTK inhibitors can be examined at the molecular, cellular, and organismal levels.

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