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Inhibition of mRNA translation initiation factors as novel therapeutic approach in chronic lymphocytic leukaemia (CLL)

Inhibition of mRNA translation initiation factors as novel therapeutic approach in chronic lymphocytic leukaemia (CLL)
Inhibition of mRNA translation initiation factors as novel therapeutic approach in chronic lymphocytic leukaemia (CLL)
Signalling via the B-cell receptor (BCR) is a major driver of disease progression in chronic lymphocytic leukaemia (CLL) and an established target for therapeutic attack. Studies have demonstrated that BCR-stimulation of CLL cells leads to a substantial increase in global mRNA translation and enhanced translation of oncoprotein MYC. Increased translation is associated with increased expression of eukaryotic initiation factor-4A (eIF4A) in CLL cells, but not in healthy donor B cells, and high expression of eIF4E has been documented in CLL compared to normal B cells. This suggested that it may be possible to selectively inhibit global and/or MYC mRNA translation in CLL cells using inhibitors targeted against specific components of the translation machinery. I therefore investigated the effects of inhibitors of eIF4A, silvestrol and rocaglamide, and an eIF4E inhibitor, ribavirin in CLL.

Both eIF4A inhibitors (eIF4Ai) and ribavirin reduced anti-IgM-induced global mRNA translation in primary CLL cells, analysed using O-propargy 1-puromycin (OPP)-labelling. Inhibition of eIF4A resulted in reduced translation of MYC, as well as MCL1, a BCL-2 family protein which, like MYC, is linked to poor outcome. Whilst MYC protein expression was reduced, this was associated with a surprising increase in MYC mRNA expression, via increased RNA stabilisation. Although, eIF4Ai inhibited mRNA translation in healthy donor B cells, inhibition of eIF4E had no effect on translation in B cells from healthy donors. eIF4E also has a role in the nuclear export of specific eIF4E-target mRNAs, including MYC. Ribavirin reduced the nuclear export of mRNA encoding proliferation promoting CCND1 and MYC in CLL samples. In vivo studies utilising ribavirin treatment in mice bearing Eμ-TCL1 leukaemic cells, showed efficacy by reduced tumour burden. Overall, these results support the hypothesis that inhibition of the translation initiation machinery is an effective strategy to suppress anti-IgM-induced translation in CLL cells, to deprive malignant cells of the tumour-promoting effects of oncoproteins such as MYC and MCL1.
University of Southampton
Wilmore, Sarah Catherine
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Wilmore, Sarah Catherine
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Packham, Graham
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Yeomans, Alison
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Coldwell, Mark
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Wilmore, Sarah Catherine (2020) Inhibition of mRNA translation initiation factors as novel therapeutic approach in chronic lymphocytic leukaemia (CLL). University of Southampton, Doctoral Thesis, 341pp.

Record type: Thesis (Doctoral)

Abstract

Signalling via the B-cell receptor (BCR) is a major driver of disease progression in chronic lymphocytic leukaemia (CLL) and an established target for therapeutic attack. Studies have demonstrated that BCR-stimulation of CLL cells leads to a substantial increase in global mRNA translation and enhanced translation of oncoprotein MYC. Increased translation is associated with increased expression of eukaryotic initiation factor-4A (eIF4A) in CLL cells, but not in healthy donor B cells, and high expression of eIF4E has been documented in CLL compared to normal B cells. This suggested that it may be possible to selectively inhibit global and/or MYC mRNA translation in CLL cells using inhibitors targeted against specific components of the translation machinery. I therefore investigated the effects of inhibitors of eIF4A, silvestrol and rocaglamide, and an eIF4E inhibitor, ribavirin in CLL.

Both eIF4A inhibitors (eIF4Ai) and ribavirin reduced anti-IgM-induced global mRNA translation in primary CLL cells, analysed using O-propargy 1-puromycin (OPP)-labelling. Inhibition of eIF4A resulted in reduced translation of MYC, as well as MCL1, a BCL-2 family protein which, like MYC, is linked to poor outcome. Whilst MYC protein expression was reduced, this was associated with a surprising increase in MYC mRNA expression, via increased RNA stabilisation. Although, eIF4Ai inhibited mRNA translation in healthy donor B cells, inhibition of eIF4E had no effect on translation in B cells from healthy donors. eIF4E also has a role in the nuclear export of specific eIF4E-target mRNAs, including MYC. Ribavirin reduced the nuclear export of mRNA encoding proliferation promoting CCND1 and MYC in CLL samples. In vivo studies utilising ribavirin treatment in mice bearing Eμ-TCL1 leukaemic cells, showed efficacy by reduced tumour burden. Overall, these results support the hypothesis that inhibition of the translation initiation machinery is an effective strategy to suppress anti-IgM-induced translation in CLL cells, to deprive malignant cells of the tumour-promoting effects of oncoproteins such as MYC and MCL1.

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Published date: January 2020

Identifiers

Local EPrints ID: 439325
URI: http://eprints.soton.ac.uk/id/eprint/439325
PURE UUID: d27abae7-2657-4fe5-b825-f9a71a179707
ORCID for Sarah Catherine Wilmore: ORCID iD orcid.org/0000-0002-6929-0267
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for Mark Coldwell: ORCID iD orcid.org/0000-0002-6243-3886

Catalogue record

Date deposited: 08 Apr 2020 16:40
Last modified: 17 Mar 2024 05:22

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Contributors

Author: Sarah Catherine Wilmore ORCID iD
Thesis advisor: Graham Packham ORCID iD
Thesis advisor: Alison Yeomans
Thesis advisor: Mark Coldwell ORCID iD

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