title: Inverse regulation of bridging integrator 1 and BCR-ABL1 in chronic myeloid leukemia.
abstract: Endocytosis is the major regulator process of tyrosine kinase receptor (RTK) functional activities. Bridging integrator 1 (BIN1) is a key protein involved in RTK intracellular trafficking. Here, we report, by studying 34 patients with chronic myeloid leukemia (CML) at diagnosis, that BIN1 gene is downregulated in CML as compared to healthy controls, suggesting an altered endocytosis of RTKs. Rab interactor 1 (RIN1), an activator of BIN1, displayed a similar behavior. Treatment of 57 patients by tyrosine kinase inhibitors caused, along with BCR-ABL1 inactivation, an increase of BIN1 and RIN1 expression, potentially restoring endocytosis. There was a significant inverse correlation between BIN1-RIN1 and BCR-ABL1 expression. In vitro experiments on both CML and nontumorigenic cell lines treated with Imatinib confirmed these results. In order to provide another proof in favor of BIN1 and RIN1 endocytosis function in CML, we demonstrated that Imatinib induced, in K562 cell line, BIN1-RIN1 upregulation accompanied by a parallel AXL receptor internalization into cytoplasmic compartment. This study shows a novel deregulated mechanism in CML patients, indicating BIN1 and RIN1 as players in the maintenance of the abnormal RTK signaling in this hematological disease.
authors.affiliation: Laboratory of Pre-clinical and Translational Research, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy. stefania.trino@crob.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Trino
authors.affiliation: Laboratory of Pre-clinical and Translational Research, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: De Luca
authors.affiliation: Laboratory of Pre-clinical and Translational Research, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Simeon
authors.affiliation: Laboratory of Pre-clinical and Translational Research, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Laurenzana
authors.affiliation: Laboratory of Pre-clinical and Translational Research, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Morano
authors.affiliation: Laboratory of Pre-clinical and Translational Research, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Caivano
authors.affiliation: Laboratory of Pre-clinical and Translational Research, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: La Rocca
authors.affiliation: Department of Onco-Hematology, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pietrantuono
authors.affiliation: Laboratory of Clinical Research and Advanced Diagnostics, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Bianchino
authors.affiliation: Laboratory of Clinical Research and Advanced Diagnostics, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
authors.forename: Vitina
authors.initials: V
authors.lastname: Grieco
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Signorino
authors.affiliation: Hematology Unit, Ospedale Madonna delle Grazie, ASM, Matera, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Fragasso
authors.affiliation: Institute of Hematology "L. e A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bochicchio
authors.affiliation: Institute of Hematology "L. e A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Venturi
authors.affiliation: Institute of Hematology "L. e A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Gianantonio
authors.initials: G
authors.lastname: Rosti
authors.affiliation: Institute of Hematology "L. e A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.affiliation: Biotecnologie Avanzate, CEINGE, Naples, Italy.|Department of Molecular Medicine and Medical Biotechnologies, "Federico II" University of Naples, Naples, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Del Vecchio
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cilloni
authors.affiliation: Scientific Direction, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
authors.forename: Pellegrino
authors.initials: P
authors.lastname: Musto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology; D003593:Cytoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004705:Endocytosis; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C092117:RIN1 protein, human; D025521:Tumor Suppressor Proteins; D020794:Receptor Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
keywords: AXL; BCR-ABL1; Bridging integrator 1; Chronic myeloid leukemia; Rab interactor 1