Irradiation of the microenvironment affects epigenetic therapy by LSD1 inhibition in murine AML model

Mariggi, Maria Despoina (2025): Irradiation of the microenvironment affects epigenetic therapy by LSD1 inhibition in murine AML model. Dissertation, LMU München: Medizinische Fakultät

Abstract

Irradiation of bone marrow is an important aspect in treating Acute myeloid leukemia (AML). Chemotherapy (in combination with additional substances) is often not enough to achieve a long-lasting complete remission. Because of that an allogenic stem cell transplantation is required, which is often done after a total body irradiation. Moreover, in experimental leukemia research, total body irradiation of lab animals (e.g. mice) is often implemented to achieve better cell engraftment. Currently, many aspects of the irradiated bone marrow microenvironment are still unknown. Therefore, the focus of this thesis encompasses the mechanisms of how an irradiated microenvironment influences epigenetic therapy with the inhibitor of the lysine specific demethylase 1 (LSD1i). The AML subgroup emerging from the MLL-AF9 fusion was specifically examined. Syngeneic mice were transplanted in previous experiments with MLL-AF9 positive AML cells. Prior to transplantation, some of the mice were sublethally irradiated and some were not irradiated. The irradiated group responded to LSD1i therapy and showed a longer overall survival. In contrast, the not irradiated group did not respond to the therapy and had a shorter overall survival. Simplified in-vitro experiments with mesenchymal stem cells (MSC) were carried out to further investigate this bone marrow phenomenon, as well as co-culture experiments with AML cells. The results suggest that in-vitro irradiated and with LSD1i treated MSCs have an altered transcriptome in comparison to normal MSCs. RNA-Sequencing results show that after irradiation and treatment of MSC with LSD1i there are 606 differentially deregulated genes in relation to untreated and not irradiated MSC. This altered transcriptome led to loss of stem cell features in the stromal cells and induced differentiation. Irradiation of MSCs leads most likely to adipogenesis. Furthermore, there was supporting evidence that the irradiation-dependent LSD1i resistance could be mediated by the cytokine CCL5. Lastly, the protective effect of stromal cells, independent of irradiation, could be demonstrated in-vitro.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 25. März 2025
• 1. Bericht­erstatter:in: Greif, Philipp