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Haematologica. 2020 Jan 31;105(2):387-397. doi: 10.3324/haematol.2019.219394. Print 2020.

Validation of a Drosophila model of wild-type and T315I mutated BCR-ABL1 in chronic myeloid leukemia: an effective platform for treatment screening.

Author information

1
Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut.
2
Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut.
3
Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
4
Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut ms241@aub.edu.lb.
5
Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut ms241@aub.edu.lb.

Abstract

Chronic myeloid leukemia is caused by a balanced chromosomal translocation resulting in the formation of BCR-ABL1 fusion gene encoding a constitutively active BCR-ABL1 tyrosine kinase, which activates multiple signal transduction pathways leading to malignant transformation. Standard treatment of chronic myeloid leukemia is based on tyrosine kinase inhibitors; however, some mutations have proven elusive particularly the T315I mutation. Drosophila melanogaster is an established in vivo model for human diseases including cancer. The targeted expression of chimeric human/fly and full human BCR-ABL1 in Drosophila eyes has been shown to result in detrimental effects. In this study, we expressed human BCR-ABL1p210 and the resistant BCR-ABL1p210/T315I fusion oncogenes in Drosophila eyes. Expression of BCR-ABL1p210/T315I resulted in a severe distortion of the ommatidial architecture of adult eyes with a more prominent rough eye phenotype compared to milder phenotypes in BCR-ABL1p210 reflecting a stronger oncogenic potential of the mutant. We then assessed the efficacy of the currently used tyrosine kinase inhibitors in BCR-ABL1p210 and BCR-ABL1p210/T315I expressing flies. Treatment of BCR-ABL1p210 expressing flies with potent kinase inhibitors (dasatinib and ponatinib) resulted in the rescue of ommatidial loss and the restoration of normal development. Taken together, we provide a chronic myeloid leukemia tailored BCR-ABL1p210 and BCR-ABL1p210/T315I fly model which can be used to test new compounds with improved therapeutic indices.

PMID:
31101753
DOI:
10.3324/haematol.2019.219394
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