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Expression of chronic myeloid leukemia oncogenes BCR-ABL (P210) and BCR-ABL (T315I) affect cellular and humoral innate immunity in Drosophila melanogaster

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that results from a chromosomal translocation between chromosome 9 and chromosome 22. The resulting fusion gene ( BCR-ABL ) encodes a constitutively active BCR-ABL tyrosine kinase. Some mutations of this oncogene, especially the Threoni...

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Detalles Bibliográficos
Autores principales: Abubaker, Dana, Baassiri, Amro, Ghannam, Mirna, Al Outa, Amani, Ghais, Ali, Rahal, Elias, Nasr, Rihab, Shirinian, Margret
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Caltech Library 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9008464/
https://www.ncbi.nlm.nih.gov/pubmed/35622506
http://dx.doi.org/10.17912/micropub.biology.000551
Descripción
Sumario:Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that results from a chromosomal translocation between chromosome 9 and chromosome 22. The resulting fusion gene ( BCR-ABL ) encodes a constitutively active BCR-ABL tyrosine kinase. Some mutations of this oncogene, especially the Threonine 315 to Isoleucine substitution of the ABL kinase is resistant to first and second-generation tyrosine kinase inhibitors (TKIs) conventionally used in CML therapy. We have previously validated a CML fruit fly model for drug screening using the adult fly compound eye. Here we expressed wild-type BCR-ABL (P210) and mutated BCR-ABL (T315I) in Drosophila melanogaster hematopoietic system to understand the phenotypic consequences of this expression and its impact on innate immune pathways. Flies expressing both wild-type BCR-ABL (P210) and mutant BCR-ABL (T315I) showed increased number of circulating hemocytes, disruption in sessile patterning of resident hemocytes, dysregulation in the humoral Toll, ImD, and JAK/STAT pathways at the mRNA level in both the 3 (rd) instar larva and adult stages. Of note, BCR-ABL (T315I) flies presented more severe phenotypes and a higher deviation in humoral dysregulation than BCR -ABL (P210) flies pointing towards more complex oncogenic effect of this mutant which requires further investigation.