Journal
ONCOGENE
Volume 32, Issue 2, Pages 198-208Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.42
Keywords
Rho GTPases; acute lymphoblastic leukaemia; Notch1; RhoU; cell migration; cytoskeleton
Funding
- Leukaemia and Lymphoma Research UK
- Cancer Research UK
- King's College London British Heart Foundation Centre of Excellence
- Department of Health via National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre
- King's College London
- King's College Hospital NHS Foundation Trust
- Cancer Research UK [15961] Funding Source: researchfish
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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 gamma-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. Oncogene (2013) 32, 198-208; doi:10.1038/onc.2012.42; published online 20 February 2012
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