Percy, LA; (2015) Exploring mechanisms of drug resistance in multiple myeloma: the roles of the progenitor compartment, APRIL and Notch signalling. Doctoral thesis , UCL (University College London).

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Abstract

Multiple myeloma (MM) is characterised by the proliferation of clonal plasma cells and a number of novel, highly effective anti-MM agents have improved long-term survival. However, eventually all patients become resistant and the disease remains incurable. The occurrence of disease relapse after the apparent eradication of the clonal population indicates the persistent survival of a drug resistant, ‘progenitor’ subpopulation. Understanding the mechanisms that underlie these patterns of resistance, including the characterisation of MM progenitors, is therefore critical to improving clinical outcomes. A cancer stem cell model has been proposed in the context of MM, based on the lack of syndecan-1 (CD138) in clonal, light chainrestricted cells. This work did not substantiate this claim, and data from a series of primary samples suggest that lack of CD138 is not a robust marker for a progenitor population of MM cells. The bone marrow (BM) microenvironment is known to play a critical part in MM cell survival and resistance, mediated by cytokines present within MM cell niches, and by cell-contact dependent pathways activated in MM cells and within adjacent supportive BM cells. This work examines the role of A Proliferation-Inducing Ligand (APRIL), and of the Notch signalling pathway. The data suggest that soluble APRIL confers protection against Dexamethasone-induced apoptosis, whilst the Notch ligand Delta-like ligand-1, expressed on the stromal cell line, HS-5, enhances stroma-mediated protection against bortezomib.

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