The matricellular protein CCN3 regulates NOTCH1 signalling in chronic myeloid leukaemia

Sukanya Suresh, Lynn McCallum, Lisa J Crawford, Wan Hua Lu, Daniel J Sharpe, Alexandra E Irvine

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
188 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)378-87
Number of pages10
JournalJournal of Pathology
Volume231
Issue number3
Early online date09 Oct 2013
DOIs
Publication statusPublished - Nov 2013

Bibliographical note

2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Keywords

  • Antineoplastic Agents
  • Benzamides
  • Flow Cytometry
  • Fusion Proteins, bcr-abl
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Nephroblastoma Overexpressed Protein
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • RNA, Small Interfering
  • Real-Time Polymerase Chain Reaction
  • Receptor, Notch1
  • Signal Transduction
  • Transfection

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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