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Chronic Myeloid Leukemia
Validation of a Drosophila model of wild-type and T315I mutated BCR-ABL1 in chronic myeloid leukemia: an effective platform for treatment screening
Ferrata Storti Foundation
Haematologica 2018 Volume 105(2):387-397
Amani Al Outa,1 Dana Abubaker,2 Ali Bazarbachi,1,3 Marwan El Sabban,1 Margret Shirinian2 and Rihab Nasr1
1Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut; 2Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut and 3Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
ABSTRACT
Chronic myeloid leukemia (CML) is caused by a balanced chromo- somal 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 CML is based on tyro- sine kinase inhibitors (TKI); however, some mutations have proven elu- sive particularly the T315I mutation. Drosophila melanogaster is an estab- lished 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 TKI 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 CML tailored BCR-ABL1p210 and BCR-ABL1p210/T315I fly model which can be used to test new compounds with improved therapeutic indices.
Introduction
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm secondary to a precise cytogenetic abnormality involving a balanced chromosomal translocation between the Abelson murine leukemia (ABL1) gene on chromosome 9 and the breakpoint cluster region (BCR) on chromosome 22. This creates the (BCR-ABL1) fusion gene on chromosome 22 which encodes a constitutively active tyrosine kinase BCR-ABL.1 Based on the breakpoints in BCR this translocation results in the formation of (p190, p210 and p230) fusion genes.2 Overall, 95% of CML patients harbor the p210-kDa fusion protein, BCR-ABL1p210.3,4 The BCR-ABL1 fusion onco- protein increases the replication machinery and enhances cell growth which is mediated by downstream signaling pathways such as RAS, RAF, JUN kinase, MYC and STAT.5-11
CML treatment was revolutionized with the development of tyrosine kinase inhibitors (TKI) which competitively inhibit the Adenosine triphosphate (ATP) binding site in the BCR-ABL1 kinase domain12 and hence block the phosphoryla- tion of proteins in the downstream signaling cascade. The first generation TKI (imatinib) showed major therapeutic improvement in the IRIS study (International Randomized Study of Interferon and STI571).13 However, imatinib success was
Correspondence:
MARGRET SHIRINIAN
ms241@aub.edu.lb
RIHAB NASR
rn03@aub.edu.lb
Received: February 15, 2019. Accepted: May 16, 2019. Pre-published: May 17, 2019.
doi:10.3324/haematol.2019.219394
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/2/387
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haematologica | 2020; 105(2)
387
ARTICLE