Grandage, V.L.; (2007) Investigation of aberrant signal transduction in acute myeloid leukaemia. Doctoral thesis , University of London.

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Abstract

Haematopoiesis is the result of tightly regulated signal transduction pathways mediated by cytokines and their receptors. Aberrations in these pathways are an underlying cause for diseases such as leukaemia and other myeloproliferative and lymphoproliferative disorders. The PI3-Kinase/Akt pathway is central to regulation of cell survival and proliferation. This study found that the PI3-Kinase pathway is activated in AML cells. This activation was reduced or abolished when the cells were incubated with the PI3-Kinase inhibitor, LY294002. Leukaemic cell survival appeared to be dependent on PI3-Kinase activation as incubation with LY294002 resulted in a reduction in cell number and an increase in apoptosis. This was also true for the CD34+/38- leukaemic stem cell population. Further work indicated that activation of Akt alone was sufficient to protect factor dependent cells from cytokine withdrawal induced apoptosis and also from the cytotoxic effects of Ara-C and Etoposide. The JAK/ STAT Pathway is important for many biological responses including differentiation and proliferation and its dysregulation has also been reported in many malignancies. It was shown that G66976, a selective PKC inhibitor, is a potent inhibitor of JAK 2 in in vitro kinase assays and in whole cell systems and inhibits signaling downstream of multiple JAK2 coupled cytokines including IL-3, GM-CSF and EPO. G66976 was also found to inhibit signalling downstream of disease-associated forms of JAK2 such as the TEL-JAK2 fusion and mutant JAK2 V617F. The majority of primary AML cells investigated had constitutive STAT activation which was reduced by incubation with G66976 in the majority of cases. This reduction was accompanied by a decrease in cell survival and proliferation. This work indicates that both the PI3-Kinase/Akt and the JAK/STAT pathways would be appropriate targets for the development of small molecule inhibitors for use in the treatment of AML.

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