title: Notch1 regulates chemotaxis and proliferation by controlling the CC-chemokine receptors 5 and 9 in T cell acute lymphoblastic leukaemia.
abstract: Tumour cells often express deregulated profiles of chemokine receptors that regulate cancer cell migration and proliferation. Notch1 pathway activation is seen in T cell acute lymphoblastic leukaemia (T-ALL) due to the high frequency of Notch1 mutations affecting approximately 60% of patients, causing ligand-independent signalling and/or prolonging Notch1 half-life. We have investigated the possible regulative role of Notch1 on the expression and function of chemokine receptors CCR5, CCR9 and CXCR4 that play a role in determining blast malignant properties and localization of extramedullary infiltrations in leukaemia. We inhibited the pathway through γ-Secretase inhibitor and Notch1 RNA interference and analysed the effect on the expression and function of chemokine receptors. Our results indicate that γ-Secretase inhibitor negatively regulates the transcription level of the CC chemokine receptors 5 and 9 in T-ALL cell lines and patients' primary leukaemia cells, leaving CXCR4 expression unaltered. The Notch pathway also controls CCR5- and CCR9-mediated biological effects, ie chemotaxis and proliferation. Furthermore, engaging CCR9 through CCL25 administration rescues proliferation inhibition associated with abrogation of Notch activity. Finally, through RNA interference we demonstrated that the oncogenic isoform in T-ALL, Notch1, plays a role in controlling CCR5 and CCR9 expression and functions. These findings suggest that Notch1, acting in concert with chemokine receptors pathways, may provide leukaemia cells with proliferative advantage and specific chemotactic abilities, therefore influencing tumour cell progression and localization.
authors: Department of Medicine, Surgery and Dentistry, Università degli Studi di Milano, Milan, Italy.
authors: Leonardo
authors: L
authors: Mirandola
authors: Maurizio
authors: M
authors: Chiriva-Internati
authors: Daniela
authors: D
authors: Montagna
authors: Franco
authors: F
authors: Locatelli
authors: Marco
authors: M
authors: Zecca
authors: Marco
authors: M
authors: Ranzani
authors: Andrea
authors: A
authors: Basile
authors: Massimo
authors: M
authors: Locati
authors: Everardo
authors: E
authors: Cobos
authors: W Martin
authors: WM
authors: Kast
authors: Rosanna
authors: R
authors: Asselta
authors: Elvezia Maria
authors: EM
authors: Paraboschi
authors: Paola
authors: P
authors: Comi
authors: Raffaella
authors: R
authors: Chiaramonte
mesh_terms: D000293:Adolescent; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019742:Chemokines, CC / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D054388:Receptors, CCR / Q000235:genetics / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: C119309:CC chemokine receptor 9; C108074:CCL25 protein, human; C527276:CXCR4 protein, human; D019742:Chemokines, CC; D004791:Enzyme Inhibitors; C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D051881:Receptor, Notch1; D054388:Receptors, CCR; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D053829:Amyloid Precursor Protein Secretases