title: New alternative splicing BCR/ABL-OOF shows an oncogenic role by lack of inhibition of BCR GTPase activity and an increased of persistence of Rac activation in chronic myeloid leukemia.
abstract: In Chronic Myeloid Leukemia 80% of patients present alternative splice variants involving BCR exons 1, 13 or 14 and ABL exon 4, with a consequent impairment in the reading frame of the ABL gene. Therefore BCR/ABL fusion proteins (BCR/ABL-OOF) are characterized by an in-frame BCR portion followed by an amino acids sequence arising from the out of frame (OOF) reading of the ABL gene. The product of this new transcript contains the characteristic BCR domains while lacking the COOH-terminal Rho GTPase GAP domain. The present work aims to characterize the protein functionality in terms of cytoskeleton (re-)modelling, adhesion and activation of canonical oncogenic signalling pathways. Here, we show that BCR/ABL-OOF has a peculiar endosomal localization which affects EGF receptor activation and turnover. Moreover, we demonstrate that BCR/ABL-OOF expression leads to aberrant cellular adhesion due to the activation of Rac GTPase, increase in cellular proliferation, migration and survival. When overexpressed in a BCR/ABL positive cell line, BCR/ABL-OOF induces hyperactivation of Rac signaling axis offering a therapeutic window for Rac-targeted therapy. Our data support a critical role of BCR/ABL-OOF in leukemogenesis and identify a subset of patients that may benefit from Rac-targeted therapies.
authors.affiliation: Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Panuzzo
authors.affiliation: Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
authors.forename: Gisella
authors.initials: G
authors.lastname: Volpe
authors.affiliation: Department of Oncology, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cibrario Rocchietti
authors.affiliation: Department of Medical Biotechnologies and Translational Medicine, School of Medicine, University of Milan, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Casnici
authors.affiliation: Department of Medical Biotechnologies and Translational Medicine, School of Medicine, University of Milan, Milan, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Crotta
authors.affiliation: Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Crivellaro
authors.affiliation: Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Carrà
authors.affiliation: Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Lorenzatti
authors.affiliation: Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Peracino
authors.affiliation: Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Torti
authors.affiliation: Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Morotti
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Maria Pilar
authors.initials: MP
authors.lastname: Camacho-Leal
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Defilippi
authors.affiliation: Department of Medical Biotechnologies and Translational Medicine, School of Medicine, University of Milan, Milan, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Marelli
authors.affiliation: Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
keywords: BCR-ABL; Chronic Myeloid Leukemia; Rac GTPase; alternative splicing