Gronthos, StanHiwase, DevendraKutyna, Monika Maria2023-01-062023-01-062022https://hdl.handle.net/2440/137174Therapy-related myeloid neoplasm (tMN), lethal blood cancer developing in long-term cancer survivors, is considered to be direct consequence of cytotoxic therapy-induced DNA damage in haematopoietic stem cells. Despite increased recognition that altered bone marrow stroma can also drive leukemogenesis, the functional biology of tMN bone marrow microenvironment remains unknown. Comprehensive multiomic (transcriptome, DNA damage response, cytokine secretome and functional profiling) characterisation of bone marrow stromal cells from tMN was performed and compared with (i) patients with myeloid neoplasm and a history of another cancer but without cytotoxic exposure, (ii) typical primary myeloid neoplasm and (iii) agematched controls, to decipher bone marrow microenvironmental changes induced by cytotoxics from that age related and myeloid neoplasm induced changes. tMN bone marrow mesenchymal stromal cells exhibited profound senescence with CDKN1A induction, high levels of β-Galactosidase, aberrant morphology, defective proliferation, differentiation and haematopoietic stem cell supportive capacity. Highly senescence phenotype is probably driven by defective DNA repair capacity. Strikingly, despite their dormant state, tMN stromal cells were metabolically highly active with a switch towards glycolysis and secreted multiple pro-inflammatory cytokines indicative of a senescent-secretory phenotype that inhibited adipogenesis. Critically, senolytics not only eliminated dormant cells, but also restored adipogenesis. Finally, sequential patient sampling showed senescence phenotypes are induced within months of cytotoxic exposure, well prior to the onset of secondary cancer. This thesis provides novel insight into role of pro-inflammatory and senescent stromal milieu to tMN pathogenesis and provide a valuable resource for future strategies to delay/prevent the tMN.enbone marrow stromamesenchymal stromal cellstherapy related myeloid neoplasmsThesis