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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-ABL1 p210 and the resistant BCR-ABL1 p210/T315I fusion oncogenes in Drosophila eyes. Expression of BCR-ABL1 p210/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-ABL1 p210 reflecting a stronger oncogenic potential of the mutant. We then assessed the efficacy of the currently used tyrosine kinase inhibitors in BCR-ABL1 p210 and BCR-ABL1 p210/T315I expressing flies. Treatment of BCR-ABL1 p210 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-ABL1 p210 and BCR-ABL1 p210/T315I fly model which can be used to test new compounds with improved therapeutic indices.

haematologica

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

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