The Molecular regulation of apoptosis in b-cell neoplasms

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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Identifiers

ORCID for Mark Cragg: orcid.org/0000-0003-2077-089X

ORCID for Graham Packham: orcid.org/0000-0002-9232-5691

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