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

Author information

Affiliations

  • 1. Department of Laboratory Medicine, Translational Research Center Karolinska (TRACK), Karolinska Institutet, Karolinska University Hospital, SE-141 86 Stockholm, Sweden.
      Authors
    • Hamada-Kawaguchi N 1, 3
    • Zain R 1
    • Smith CIE 1
    (3 authors)
  • 2. Food Science Technology, School of Applied Sciences and Mathematics (SASM), University Technology Brunei (UTB), BE1410 Mukim Gadong A, Brunei Darussalam.
      Authors
    • Nore BF 2
    (1 author)
  • 3. Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden.
      Authors
    • Hamada-Kawaguchi N 1, 3
    • Engström Y 3
    (2 authors)
  • 4. Neuro-ICT Laboratory, Advanced Institute of Information and Communications Technology, 651-2492 Kobe, Japan.
      Authors
    • Yamamoto D 4
    (1 author)

Frontiers in Bioscience (Landmark Edition), 01 Jun 2023, 28(6):124
https://doi.org/10.31083/j.fbl2806124 PMID: 37395037 

Abstract 

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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Read article at publisher's site: https://doi.org/10.31083/j.fbl2806124

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