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Chronic Myeloid Leukemia
A new BCR-ABL1 Drosophila model as
a powerful tool to elucidate the pathogenesis and progression of chronic myeloid leukemia
Roberto Bernardoni,1,2,§,# Giorgia Giordani,1,3,4,§ Elisabetta Signorino,3,§
Sara Monticelli,1 Francesca Messa,1 Monica Pradotto,3 Valentina Rosso,3 Enrico Bracco,5 Angela Giangrande,6 Giovanni Perini,1,2* Giuseppe Saglio3,* and Daniela Cilloni3,*#
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 pro- moters. 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 expres- sion 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.
Introduction
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder asso- ciated with a reciprocal translocation between chromosomes 9 and 22. This process leads to the fusion of the Abelson (ABL1) tyrosine kinase gene with the breakpoint cluster region (BCR) sequences generating a fusion gene encoding the constitutively active protein tyrosine kinase BCR-ABL1. Due to its high frequen- cy in CML patients (95%), the translocation is considered the cytogenetic hall- mark of this disease.1,2 Although BCR-ABL1 is one of the most studied oncogenic proteins, some molecular mechanisms leading to cellular transformation are still partially unknown. In particular, positive or negative regulators of BCR-ABL1 have not been completely identified. The fruitfly, Drosophila melanogaster, repre- sents a powerful tool for genome-wide genetic analysis and screens, given the functional conservation and sequence homology between human and Drosophila genes. Genome-wide approaches may allow identification of genetic pathways that contribute to disease onset and/or progression without a priori knowledge of the gene function.3 The high degree of conservation between human and
Ferrata Storti Foundation
Haematologica 2019 Volume 104(4):717-728
1Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Italy; 2Health Sciences and Technology - Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Ozzano Emilia, Italy; 3Department of Clinical and Biological Sciences, University of Turin, Italy; 4Present address: Department of Biological Sciences, School of Applied Sciences, University of Huddersfield, Queensgate, UK; 5Department of Oncology, University of Turin, Italy and 6Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP 67404 Illkirch, France
§These authors share first authorship. *These authors share last authorship.
Correspondence:
DANIELA CILLONI
daniela.cilloni@unito.it
ROBERTO BERNARDONI
roberto.bernardoni@unibo.it
Received: May 21, 2018. Accepted: November 8, 2018. Pre-published: November 8, 2018.
doi:10.3324/haematol.2018.198267
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/4/717
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