Investigations into the protective effects of the Multiple Myeloma Bone Marrow Microenvironment

Piddock, Rachel (2018) Investigations into the protective effects of the Multiple Myeloma Bone Marrow Microenvironment. Doctoral thesis, University of East Anglia.

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Abstract

Multiple Myeloma (MM) is the second most common haematological cancer in the Western World, accounting for approximately 10% of all newly diagnosed blood cancers each year. Despite the recent advancements in its treatment, MM remains incurable. This is partly due to the protective niche in which it inhabits – the bone marrow microenvironment (BMM). MM cells have been shown to `re-program’ other cell populations within this milieu to produce the growth factors needed for its own development. These factors initiate pro-survival pathways within MM cells, including the phosphatidylinositol 3-kinase (PI3K) pathway. The PI3K catalytic isoforms p110δ and p110γ are known to be specifically enriched by the haematopoietic system, providing a highly precise therapeutic target.
In this thesis, the PI3K pathway was shown to be activated in response to both the BMM and IL-6 alone. Both p110δ/p110γ were found to be highly expressed in MM and were implicated in MM growth, survival and migration. p110γ only knockdown within human MM cell lines caused a significant reduction in MM adhesion to fibronectin. In vivo, xenograft models showed that knockdown of either of these isoforms in the human MM cell line U266 increased overall survival (OS), as did dual inhibition of p110δ and p110γ (via the drug IPI-145).
Cytokine array analysis of MM primary cells revealed extremely high levels of extracellular Macrophage Migratory Inhibitory Factor (MIF), a known stimulator of the PI3K pathway. Knockdown of MM cell MIF resulted in significantly increased OS and reduced tumour burden in secondary sites. MIF was found to stimulate the production of IL-6/8 from bone marrow stromal cells, and c-Myc was implicated in the regulation of this process.
Taken together, the data presented here demonstrates that PI3K signalling is beneficial to MM disease progression. MM-derived MIF increases the availability of IL-6 within the BMM, causing activation of the PI3K pathway. Therapies targeting the PI3K isoforms or MIF (alongside conventional MM therapeutics) could therefore benefit MM patient treatment, and warrants clinical investigation.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Bruce Beckett
Date Deposited: 20 Jul 2018 13:58
Last Modified: 20 Jul 2018 13:58
URI: https://ueaeprints.uea.ac.uk/id/eprint/67702
DOI:

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