title: The matricellular protein CCN3 regulates NOTCH1 signalling in chronic myeloid leukaemia.
abstract: Deregulated NOTCH1 has been reported in lymphoid leukaemia, although its role in chronic myeloid leukaemia (CML) is not well established. We previously reported BCR-ABL down-regulation of a novel haematopoietic regulator, CCN3, in CML; CCN3 is a non-canonical NOTCH1 ligand. This study characterizes the NOTCH1–CCN3 signalling axis in CML. In K562 cells, BCR-ABL silencing reduced full-length NOTCH1 (NOTCH1-FL) and inhibited the cleavage of NOTCH1 intracellular domain (NOTCH1-ICD), resulting in decreased expression of the NOTCH1 targets c-MYC and HES1. K562 cells stably overexpressing CCN3 (K562/CCN3) or treated with recombinant CCN3(rCCN3) showed a significant reduction in NOTCH1 signalling (> 50% reduction in NOTCH1-ICD, p < 0.05).Gamma secretase inhibitor (GSI), which blocks NOTCH1 signalling, reduced K562/CCN3 colony formation but increased that of K562/control cells. GSI combined with either rCCN3 or imatinib reduced K562 colony formation with enhanced reduction of NOTCH1 signalling observed with combination treatments. We demonstrate an oncogenic role for NOTCH1 in CML and suggest that BCR-ABL disruption of NOTCH1–CCN3 signalling contributes to the pathogenesis of CML.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Suresh
authors.forename: Lynn
authors.initials: L
authors.lastname: McCallum
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Crawford
authors.forename: Wan Hua
authors.initials: WH
authors.lastname: Lu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sharpe
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Irvine
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells / Q000187:drug effects / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism*; D055514:Nephroblastoma Overexpressed Protein / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C526319:CCN3 protein, human; C497761:NOTCH1 protein, human; D055514:Nephroblastoma Overexpressed Protein; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl