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A CML Drosophila model for treatment screening
percentage of rescue, 21% and 13% respectively; this might be attributed to the difference in the drug potencies among to of imatinib and other TKI. Compared to ima- tinib, Dasatinib exhibits a 325-fold higher potency of BCR-AB1L inhibition in vitro whereas nilotinib is only 20- fold more potent.23 Another possible explanation for the limited rescuing efficacy of imatinib and nilotinib could be the activation of dAbl by BCR-ABL1 expression shown
previously by Bernardoni et al.,34 which demonstrated that human BCR-ABL1 expression interferes with the dAbl sig- naling pathway and increases Ena phosphorylation, a dAbl target. On the other hand, using Drosophila wing epithelium as an in vivo model, Singh et al.41 demonstrated that activated dAbl exerts a positive feedback loop on Drosophila Src members leading to an increase in their activity and hence signal amplification. It is well known
Figure 7. Dasatinib and ponatinib rescue BCR-ABL1p210 driven eye defect in a dose dependent manner. Scanning electron micrographs of adult Drosophila compound eyes from flies expressing BCR-ABL1p210 and fed on 0.03% DMSO (A, E), 1 μM (B, F), 10 μM (C-G) or 20 μM (D, H) dasatinib and flies fed on 0.3% DMSO (I, L), 28 μm pona- tinib (J, M) or 280 μM ponatinib (K, N). Posterior is to the left. E-H and L-N are high magnification of the posterior end of the eye in A-D and I-K respectively (692x). Posterior eye defect area is marked with a represen- tative dashed line. Lower panels represent measurement of the posterior eye defect area (μm2) . Data represents mean ± SEM. ** P<0.01; **** P<0.0001.
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