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ZIPK mediates pre-mRNA processing in chronic lymphocytic leukaemia via histone H3 threonine 6 and threonine 11 phosphorylation

Thomas, Fraser (2020) ZIPK mediates pre-mRNA processing in chronic lymphocytic leukaemia via histone H3 threonine 6 and threonine 11 phosphorylation. PhD thesis, University of Leeds.

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Abstract

Cross-linking of the B cell receptor (BCR) induces transcriptional activation of immediate early genes (IEGs) including EGR1 and DUSP2 in chronic lymphocytic leukaemia (CLL). In this work, we have shown that this transcriptional activation correlated with histone H3 threonine 6 and 11 phosphorylation. We have identified Zipper-Interacting Protein Kinase (ZIPK/DAPK3) as the kinase mediating these histone phosphorylation marks in response to activation of the BCR signalling pathway. We show that this kinase is recruited to RNA polymerase II in an anti-IgM-dependent manner where it appears to be involved in pre-mRNA processing. Both IEG transcription and histone post-translational modifications are repressed by ibrutinib, a small molecule inhibitor used in CLL treatment. DAPK inhibition mimics Ibrutinib-induced repression of both IEG mRNA and histone H3 phosphorylation, and has anti-proliferative effects comparable to ibrutinib on CLL cells in vitro. DAPK inhibitor (DAPKi) has a broader anti-tumour effect than ibrutinib in that it can repress both anti-IgM- and CD40L- (NF-kB) dependent activation. We suggest that the broader effect of DAPKi is a result of ZIPK functioning as one of the final downstream enzymes in the transcription cascade. This is also beneficial in a clinical sense concerning disease resistance, in that ZIPK seems to function far downstream of both BTK and PLCγ2 – both of which can be mutated in ibrutinib-resistant CLL. Our data suggests that ZIPK inhibition could be an alternative to ibrutinib treatment in CLL and other DAPK1-silenced malignancies.

Item Type: Thesis (PhD)
Keywords: CLL, DAPK3, ZIPK, ibrutinib, histone phosphorylation, mRNA processing, H3T11, H3T6
Academic Units: The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Experimental Haematology (Leeds)
The University of Leeds > Faculty of Medicine and Health (Leeds)
The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds)
Identification Number/EthosID: uk.bl.ethos.805357
Depositing User: Mr Fraser Thomas
Date Deposited: 12 May 2020 15:57
Last Modified: 11 Jun 2020 09:53
URI: http://etheses.whiterose.ac.uk/id/eprint/26637

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