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Haematologica. 2019 Apr;104(4):717-728. doi: 10.3324/haematol.2018.198267. Epub 2018 Nov 8.

A new BCR-ABL1 Drosophila model as a powerful tool to elucidate the pathogenesis and progression of chronic myeloid leukemia.

Author information

1
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Italy roberto.bernardoni@unibo.it.
2
Health Sciences and Technology - Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Ozzano Emilia, Italy.
3
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Italy.
4
Department of Clinical and Biological Sciences, University of Turin, Italy.
5
Present address: Department of Biological Sciences, School of Applied Sciences, University of Huddersfield, Queensgate, UK.
6
Department of Oncology, University of Turin, Italy.
7
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP 67404 Illkirch, France.
8
Department of Clinical and Biological Sciences, University of Turin, Italy daniela.cilloni@unito.it.

Abstract

The oncoprotein BCR-ABL1 triggers chronic myeloid leukemia. It is clear that the disease relies on constitutive BCR-ABL1 kinase activity, but not all the interactors and regulators of the oncoprotein are known. We describe and validate a Drosophila leukemia model based on inducible human BCR-ABL1 expression controlled by tissue-specific promoters. The model was conceived to be a versatile tool for performing genetic screens. BCR-ABL1 expression in the developing eye interferes with ommatidia differentiation and expression in the hematopoietic precursors increases the number of circulating blood cells. We show that BCR-ABL1 interferes with the pathway of endogenous dAbl with which it shares the target protein Ena. Loss of function of ena or Dab, an upstream regulator of dAbl, respectively suppresses or enhances both the BCR-ABL1-dependent phenotypes. Importantly, in patients with leukemia decreased human Dab1 and Dab2 expression correlates with more severe disease and Dab1 expression reduces the proliferation of leukemia cells. Globally, these observations validate our Drosophila model, which promises to be an excellent system for performing unbiased genetic screens aimed at identifying new BCR-ABL1 interactors and regulators in order to better elucidate the mechanism of leukemia onset and progression.

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