Notch1 regulates chemotaxis and proliferation by controlling the CC-chemokine receptors 5 and 9 in T cell acute lymphoblastic leukaemia

Leonardo Mirandola, Maurizio Chiriva-Internati, Daniela Montagna, Franco Locatelli, Marco Zecca, Marco Ranzani, Andrea Basile, Massimo Locati, Everardo Cobos, W. Martin Kast, Rosanna Asselta, Elvezia Maria Paraboschi, Paola Comi, Raffaella Chiaramonte

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)713-722
Number of pages10
JournalJournal of Pathology
Volume226
Issue number5
DOIs
Publication statusPublished - Apr 2012

Keywords

  • CCL25
  • CCR5
  • CCR7
  • CCR9
  • Chemokine receptor
  • Chemotaxis
  • CXCR4
  • Notch
  • Proliferation
  • T cell acute lymphoblastic leukaemia

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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