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Analysis of Rho GTPase expression in T-ALL identifies RhoU as a target for Notch involved in T-ALL cell migration

Oncogene volume 32, pages 198–208 (2013)Cite this article

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Abstract

NOTCH1 is frequently mutated in T-cell acute lymphoblastic leukaemia (T-ALL), and can stimulate T-ALL cell survival and proliferation. Here we explore the hypothesis that Notch1 also alters T-ALL cell migration. Rho GTPases are well known to regulate cell adhesion and migration. We have analysed the expression levels of Rho GTPases in primary T-ALL samples compared with normal T cells by quantitative PCR. We found that 5 of the 20 human Rho genes are highly and consistently upregulated in T-ALL, and 3 further Rho genes are expressed in T-ALL but not detectable in normal T cells. Of these, RHOU expression is highly correlated with the expression of the Notch1 target DELTEX-1. Inhibition of Notch1 signalling with a γ-secretase inhibitor (GSI) or Notch1 RNA interference reduced RhoU expression in T-ALL cells, whereas constitutively active Notch1 increased RhoU expression. In addition, Notch1 or RhoU depletion, or GSI treatment, inhibits T-ALL cell adhesion, migration and chemotaxis. These results indicate that NOTCH1 mutation stimulates T-ALL cell migration through RhoU upregulation that could contribute to the leukaemia cell dissemination.

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Acknowledgements

This work was supported by Leukaemia and Lymphoma Research UK, Cancer Research UK and King's College London British Heart Foundation Centre of Excellence. EI was supported by the Department of Health via National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Award to Guy's and St Thomas’ NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. We are grateful to Sarah Heasman for scientific discussion and guidance; Ritu Garg and Katrina Soderquest for technical assistance; Katherine Lawler for advice on statistical analysis; and Matthew Arno and Estibaliz Aldecoa-otalora Astarloa for assistance and advice on qPCR.

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  1. P J Bhavsar and E Infante: These authors contributed equally to this work

Authors and Affiliations

  1. Randall Division of Cell and Molecular Biophysics, King's College London, London, UK

    P J Bhavsar, E Infante & A J Ridley

  2. National Institute for Health Research (NIHR), Biomedical Research Centre, Guy's and St Thomas’ NHS and King's College London, London, UK

    E Infante

  3. UCL Cancer Institute, University College London, London, UK

    A Khwaja

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  1. P J Bhavsar
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Correspondence to A J Ridley.

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Bhavsar, P., Infante, E., Khwaja, A. et al. Analysis of Rho GTPase expression in T-ALL identifies RhoU as a target for Notch involved in T-ALL cell migration. Oncogene 32, 198–208 (2013). https://doi.org/10.1038/onc.2012.42

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