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Targeting the splice factor kinases SRPK1 and CLK1 in leukaemia

Wodi, Chigeru

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Authors

Chigeru Wodi



Abstract

This study was aimed at investigating the effect of inhibiting SRPK1 in leukaemic cells. It was also aimed at exploring the potential utility of combining conventional leukaemia chemotherapy (such as imatinib) with compounds that inhibit SRPK1.

SRPK1 is best known for its role in the phosphorylation of serine/argenine rich proteins (SR-proteins) which are responsible for constitutive and alternative mRNA splicing. Studies have associated elevated levels of SRPK1 with tumour growth, proliferation and invasiveness with inhibition resulting in decreased tumour growth and altering the choice of alternative splice site. Imatinib mesylate and azacytidine remain the drugs of choice for the management of chronic myeloid leukaemia (CML) and acute myelogenous leukaemia (AML) respectively. Studies have shown that both imatinib and azacytidine are able to reduce the growth of proliferating Bcr/Abl+ and AML cells principally through the induction of apoptotic cell death.

SRPK1 was inhibited using the small molecule inhibitor SPHINX. SPHINX was combined with either imatinib in a CML cell line (K562) or azacytidine in an AML cell line (Kasumi-1) for up to 72hrs. Results suggest that the SPHINX compound affects the ability of SRPK1 to phosphorylate its substrates in all three cell lines (TK6, K562 and Kasumi-1). Inhibition of SRPK1 was found to reduce cell viability in Kasumi-1 cells and at higher concentration, affect K562 cell viability consistent with the work of Sanidas et al.,(2010). There was also an indication that SRPK1 could be regulating its own expression through a feedback loop in a cell line-dependent manner.

Studies with imatinib mesylate and azacytidine showed that both imatinib mesylate and azacytidine are able to reduce cell growth and viability in a dose and time-dependent manner. On combining them with SPHINX, a combination of azacytidine and SPHINX had an additive effective on Kasumi-1 cells but not with imatinib mesylate in K562 cells. Results also showed that imatinib affected the alternative splicing of caspase 9 favouring a pro-apoptotic isoform, caspase 9a. Imatinib mesylate alone also caused an apparent reduction in the expression of SRPK1, CLK1 and SRSF1, suggesting that pathways imatinib affects cell signalling pathways that regulate the expression of these oncogenic splice factor kinases and splice factors. In summary, this thesis presents evidence that targeting SRPK1 could potentially provide therapeutic benefit in the treatment of a range of leukaemias; further research is now needed to explore this novel approach.

Citation

Wodi, C. Targeting the splice factor kinases SRPK1 and CLK1 in leukaemia. (Thesis). University of the West of England. Retrieved from https://uwe-repository.worktribe.com/output/1490771

Thesis Type Thesis
Publicly Available Date Mar 28, 2024
Keywords leukaemia, SRPK1, alternative splicing, chemotherapy
Public URL https://uwe-repository.worktribe.com/output/1490771
Award Date May 27, 2021

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