title: Analysis of Rho GTPase expression in T-ALL identifies RhoU as a target for Notch involved in T-ALL cell migration.
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.
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Bhavsar
authors.forename: E
authors.initials: E
authors.lastname: Infante
authors.forename: A
authors.initials: A
authors.lastname: Khwaja
authors.forename: A J
authors.initials: AJ
authors.lastname: Ridley
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C497761:NOTCH1 protein, human; D009842:Oligopeptides; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D053829:Amyloid Precursor Protein Secretases; C432668:RHOU protein, human; D020741:rho GTP-Binding Proteins