| Summary: | The presence of correctly folded nascent immunoglobulin within the endoplasmic reticulum (ER) provides an effective checkpoint for plasma cell development. A signalling pathway called the unfolded protein response (UPR) allows cells to handle the proper folding of proteins and ensures cell survival. The transcription factor XBP1, a central control point in mediating plasma cell development is also a major regulator of the UPR providing a link between the UPR and plasma cell differentiation. My hypothesis was that inhibition of the UPR and the ER stress pathways will provide a unique differential marker which can be exploited to kill myeloma plasma cells. In order to study this, I initially characterised the role of XBP1 and IRE1a in myeloma patients and determined that the active form of XBP1, XBP1s, is an independent prognostic factor. In addition, by performing RNAi knockdown experiments I determined that suppression of the expression of XBP1 and IRE1a in myeloma cells resulted in impaired myeloma cell survival. Finally, as this study forms part of a drug discovery project aiming to therapeutically target IRE1a/XBP1, I designed and validated two assays to measure IRE1a endoribonuclease activity. Using these assays I identified a number of compounds which suppressed the kinase/endoribonuclease activity of IRE1a resulting in an impaired generation of active XBP1s and cell death. Identification of compounds which target the activity of IREa/XBP1, may therefore lead to a potential therapeutic strategy for multiple myeloma.
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