Role of Rap and Rho GTPases in T-acute lymphoblastic leukaemia cell adhesion and migration

T-acute lymphoblastic leukaemia (T-ALL) is a common childhood cancer. Multiple genetic mutations have been identified in T-ALL patients. The most common is the mutation of the NOTCH 1 oncogene occurring in more than 50% of patients. Poor prognosis has often been shown to correlate with the migration and accumulation of T-ALL cells in the tissues. Rap and Rho family GTPases play key roles in T cell adhesion and migration and are often involved in cancer progression. Most of these proteins are post-translationally isoprenylated to facilitate their anchorage to membranes, where they function to stimulate signal transduction processes. In the first part of these studies, statins were used to reduce prenylation of GTPases, and to investigate whether the resulting alteration of GTPase membrane targeting affects T-ALL cell migration. Statins inhibited adhesion, chemotaxis and transendothelial migration of T-ALL cell lines. A similar effect was observed with geranylgeranyl transferase inhibitors and siRNA depletion of Raplb but not Rap la, RhoA, Racl, Rac2 and Cdc42. These results suggest that statins and Raplb depletion could be used to reduce tissue invasion in T-ALL. In contrast to other Rho family proteins, the atypical Rho GTPases RhoU and RhoV are not prenylated but undergo palmitoylation for membrane targeting. They are expressed at higher levels in primary T-ALL samples compared to primary T cells, and RhoU expression was shown to be unregulated by Notch 1. In the second part of these studies downregulation of RhoU and Notch 1 by siRNA reduced adhesion and migration of T-ALL cell lines. Interestingly, similar functional effects were observed upon siRNA depletion of RhoV. RhoU and RhoV partially co-localized and moved dynamically between endosomes and the plasma membrane, suggesting they act together to regulate membrane trafficking. These results indicate that RhoU and RhoV could contribute to T-ALL invasion by regulating T-ALL cell adhesion and migration.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2013

Author dc:creator

• Infante, Elvira

Advisors dc:contributor.advisor

• Ridley, Anne
• Thomas, Nicholas Shaun Bevan

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/e1c1aff6-96a7-4dc6-9ee5-355bb41b01ee

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/e1c1aff6-96a7-4dc6-9ee5-355bb41b01ee