Use this URL to cite or link to this record in EThOS:
Title: The chemokine regulation of Bruton's tyrosine kinase in acute myeloid leukaemia
Author: Keadsanti, S.
ISNI:       0000 0004 7658 5316
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
Availability of Full Text:
Access from EThOS:
Access from Institution:
Acute myeloid leukaemia (AML) and chronic lymphocytic leukaemia (CLL) are common in the elderly. Bruton's tyrosine kinase (BTK) is an important protein that plays a vital role in several signalling pathways including the B cell receptor (BCR) and SDF-1α/CXCR4 chemokine signalling pathways. Although BTK is a cytoplasmic tyrosine kinase the protein can also found in the nucleus. Thus, the nuclear-cytoplasmic shuttling mechanism of BTK and BTK-binding protein are proposed in other studies, but BTK's actual role in the nucleus is still unclear. Therefore, the first aspect of this study examined BTK and p-BTK in the cytoplasm and nucleus of AML and CLL cells. AML and CLL cellular fractionation showed that BTK and p-BTK were detected in both cytoplasm and nuclear fractions. Thus, BTK may perform important functional roles in their nuclei. The second aspect of this study focused on the SDF-1α/CXCR4 signalling pathway which is important for AML survival and may control cellular responses through BTK. We identified which Gα12 subclasses can couple with CXCR4 receptor to convey the signalling of BTK, in addition to Gαi-linked signalling seen in AML. Results showed CXCR4 was expressed in AML and CLL, and that BTK is activated after SDF-1α stimulation. Therefore, our AML and CLL models express functional CXCR4. A gene silencing technique was used to identify the roles for Gα12 subclasses of G-proteins by knocking down Gα12 or Gα13 via short hairpin RNAs. The Gα12/Gα13 knockdown cells showed defective SDF-1α-induced migration responses. These results suggest that Gα12 and Gα13 can transduce signalling from SDF-1α and may be responsible of the activation of BTK in these leukaemia cells. In summary, these data reveal important new information about the role of BTK in different aspects of leukaemia cell functions and provide useful insight into the role of BTK in AML leukaemia.
Supervisor: MacEwan, David ; Slupsky, Joseph ; Pettitt, Andrew Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral