Author: Rachel Mynott
Mynott, Rachel, 2025 Investigating ferroptosis as an approach to treating multiple myeloma, Flinders University, College of Medicine and Public Health
Terms of Use: This electronic version is (or will be) made publicly available by Flinders University in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. You may use this material for uses permitted under the Copyright Act 1968. If you are the owner of any included third party copyright material and/or you believe that any material has been made available without permission of the copyright owner please contact copyright@flinders.edu.au with the details.
Multiple myeloma (MM) is an incurable haematological malignancy and while novel therapies have improved the survival of people with MM, drug resistance is inevitable. Ferroptosis is an iron-dependent form of cell death and since its first characterisation in 2012, an exponential amount of research has been undertaken showing that cancer cells are vulnerable to ferroptosis. Whilst ferroptosis has been demonstrated in MM in the literature, these cells are generally less sensitive to ferroptosis-inducing agents compared to solid tumours and other blood cancers. In this thesis we aimed to investigate the mechanisms behind ferroptosis sensitivity in MM to uncover ways in which to make them more susceptible to this unique form of cell death. We found that compared to another B-cell malignancy, diffuse large B-cell lymphoma (DLBCL), MM cell lines were generally less sensitive to the ferroptosis-inducing agent, RSL3. However, one MM cell line (OPM2) was markedly sensitive to ferroptosis. Investigating the OPM2 MM cell line further, we found that it had differential expression of ferroptosis-related genes compared to the most resistant MM cell line, KMS-11. We found that both exogenous arachidonic acid (AA) and iron could sensitise both OPM2 and KMS-11 cells to RSL3. Moreover, we discovered that inhibiting ferroptosis suppressor protein 1 (FSP1), which is not expressed in ferroptosis-sensitive OPM2 cells, was a robust way in which to sensitise KMS-11 cells to RSL3. Next, we translated our research into an ex vivo model whereby patient-derived MM cells were co-cultured with other autologous bone marrow mononuclear and stromal cells. We found that patient-derived MM cells were much more susceptible to RSL3 compared to lymphocytes and this difference in sensitivity was even more apparent when cells were supplemented with AA. We identified key genes of which expression correlated with ferroptosis sensitivity in patient-derived MM cells, as well as a higher proportion of monounsaturated fatty acid-containing phospholipids conferring resistance to cell death induced by RSL3 combined with AA. A wider range of patient-derived samples should be tested to support these conclusions, however, our findings demonstrate that MM cell lines and patient-derived MM cells can be sensitised to ferroptosis by supplementation with ferroptosis substrates such as AA. Taken together, we conclude that developing ferroptosis-inducing therapies may be a promising future strategy for treating MM.
Keywords: multiple myeloma, ferroptosis, haematology, lipid oxidation
Subject: Medical Science thesis
Thesis type: Doctor of Philosophy
Completed: 2025
School: College of Medicine and Public Health
Supervisor: Craig Wallington-Gates