A new BCR-ABL1 Drosophila model as a powerful tool to elucidate pathogenesis and progression of chronic myeloid leukemia.
Fiche publication
Date publication
novembre 2018
Journal
Haematologica
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GIANGRANDE Angela
Tous les auteurs :
Bernardoni R, Giordani G, Signorino E, Monticelli S, Messa F, Pradotto M, Rosso V, Bracco E, Giangrande A, Perini G, Saglio G, Cilloni D
Lien Pubmed
Résumé
The oncoprotein BCR-ABL1 triggers Chronic Myeloid Leukemia. It is clear that the disease relies on the constitutive BCR-ABL1 kinase activity, but not all the interactors and regulators of the oncoprotein are known. We describe and validate a Drosophila leukemia model based on inducible human BCR-ABL1 expression controlled by tissue specific promoters and thought as a versatile tool to perform genetic screens. BCR-ABL1 expression in the developing eye interferes with ommatidia differentiation and expression in the hematopoietic precursors increases the number of circulating blood cells. We show that BCR-ABL1 interferes with the pathway of endogenous dAbl with which it shares the target protein Ena. Loss of function of ena or Dab, an upstream regulator of dAbl, respectively suppresses or enhances both the BCR-ABL1 dependent phenotypes. Importantly, in patients with leukemia decrease of human Dab1 and Dab2 expression correlates with a more severe disease and Dab1 expression reduces the proliferation of leukemia cells. Globally, these observations validate our Drosophila model that promises to be an excellent system to perform unbiased genetic screens aimed at identifying new BCR-ABL1 interactors and regulators to better elucidate the mechanism of leukemia onset and progression.
Référence
Haematologica. 2018 Nov 8;: