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The Molecular regulation of apoptosis in b-cell neoplasms

The Molecular regulation of apoptosis in b-cell neoplasms
The Molecular regulation of apoptosis in b-cell neoplasms
Leukaemia and lymphoma represent the ninth and tenth most-common malignancies in the UK. Currently, therapeutic strategies utilise both chemotherapy and radiotherapy alongside the anti-CD20 monoclonal antibody Rituximab. Whilst such treatment regimes can yield impressive results, resistance and disease relapses are common. Therefore, additional therapies are required to improve patient survival and quality of life. Eliciting specific death of tumour cells and understanding the molecular mechanisms responsible provides a rational approach for developing these new therapies. One form of cell death induced in response to physiological or exogenous stress stimuli, oncogenic changes, or an absence of survival factors is termed apoptosis and is primarily regulated by the BH3-only subgroup of the Bcl-2 family.

Here, the regulation of this family of proteins was examined in a selection of murine lymphoma and leukaemia models after a selection of different apoptosis-inducing stimuli. Utilising a panel of primary murine lymphomas deficient in specific BH3-only genes, this investigation dissected the apoptotic cellular response to B cell receptor (BCR) and also TGF-β signalling. BCR signalling invoked a temporally biphasic cell death response, exhibiting both the hallmarks of apoptotic and non-apoptotic cell death. The BH3-only proteins Bim, Noxa, and Bik played key roles in BCR-induced apoptosis, whilst only Bik appeared important in the non-apoptotic phase of cell death. Such upregulation of Bim and Bik appeared dependent upon the function of ERK and Syk kinases, respectively. Thereby, identifying a link between BCR signalling and specific death effector mechanisms. TGF-β signalling, however, was linked to the induction of the BH3-only protein Puma, which played a vital role in the rapid induction of apoptosis. Finally, two new models of B cell malignancy (Tcl-1, IgHTEµ) were established and characterised in the laboratory with the aim of addressing the general suitability of the BCR as a therapeutic target and the key role of Bim in the death response.

Together, these studies further our knowledge of how BCR and TGF-β signalling evoke apoptosis in lymphoma cells, highlight the diversity of BH3-only proteins involved, and provide a series of models in which to undertake rational combination therapies.

We anticipate that the knowledge gained will help to develop future therapeutic strategies, allowing targeting of specific aspects of tumour biology, in order to improve overall patient survival.
University of Southampton
Carter, Matthew John
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Carter, Matthew John
3157f3c5-902a-4573-a100-53da9c830d7a
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394

Carter, Matthew John (2012) The Molecular regulation of apoptosis in b-cell neoplasms. University of Southampton, Doctoral Thesis, 354pp.

Record type: Thesis (Doctoral)

Abstract

Leukaemia and lymphoma represent the ninth and tenth most-common malignancies in the UK. Currently, therapeutic strategies utilise both chemotherapy and radiotherapy alongside the anti-CD20 monoclonal antibody Rituximab. Whilst such treatment regimes can yield impressive results, resistance and disease relapses are common. Therefore, additional therapies are required to improve patient survival and quality of life. Eliciting specific death of tumour cells and understanding the molecular mechanisms responsible provides a rational approach for developing these new therapies. One form of cell death induced in response to physiological or exogenous stress stimuli, oncogenic changes, or an absence of survival factors is termed apoptosis and is primarily regulated by the BH3-only subgroup of the Bcl-2 family.

Here, the regulation of this family of proteins was examined in a selection of murine lymphoma and leukaemia models after a selection of different apoptosis-inducing stimuli. Utilising a panel of primary murine lymphomas deficient in specific BH3-only genes, this investigation dissected the apoptotic cellular response to B cell receptor (BCR) and also TGF-β signalling. BCR signalling invoked a temporally biphasic cell death response, exhibiting both the hallmarks of apoptotic and non-apoptotic cell death. The BH3-only proteins Bim, Noxa, and Bik played key roles in BCR-induced apoptosis, whilst only Bik appeared important in the non-apoptotic phase of cell death. Such upregulation of Bim and Bik appeared dependent upon the function of ERK and Syk kinases, respectively. Thereby, identifying a link between BCR signalling and specific death effector mechanisms. TGF-β signalling, however, was linked to the induction of the BH3-only protein Puma, which played a vital role in the rapid induction of apoptosis. Finally, two new models of B cell malignancy (Tcl-1, IgHTEµ) were established and characterised in the laboratory with the aim of addressing the general suitability of the BCR as a therapeutic target and the key role of Bim in the death response.

Together, these studies further our knowledge of how BCR and TGF-β signalling evoke apoptosis in lymphoma cells, highlight the diversity of BH3-only proteins involved, and provide a series of models in which to undertake rational combination therapies.

We anticipate that the knowledge gained will help to develop future therapeutic strategies, allowing targeting of specific aspects of tumour biology, in order to improve overall patient survival.

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Matthew Carter Thesis - Version of Record
Available under License University of Southampton Thesis Licence.
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Published date: September 2012

Identifiers

Local EPrints ID: 436819
URI: http://eprints.soton.ac.uk/id/eprint/436819
PURE UUID: e5d8e45b-65a8-4045-8939-fb232affb526
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 10 Jan 2020 17:31
Last modified: 27 Jan 2020 13:38

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