- Leukemic Stem/Progenitor Cells and their Microenvironment: The Role of Crucial Inflammatory Factors and Bone Marrow-Derived Mesenspheres
- Forte, Dorian <1988>
Subject
- MED/15 Malattie del sangue
Description
- In this thesis, we aimed to investigate the role of inflammation in Myelofibrosis (MF) and the cross-talk between leukemic cells and their microenvironment in Acute Myeloid Leukemia (AML). In MF, we explored how inflammatory stimuli could modulate the malignant clone of HSCs. We observed potent effects of combinations of pro-inflammatory cytokines (IL-1β/ TNF-α/TIMP-1) on survival, clonogenic potential and migration of CD34+ cells isolated from MF patients at diagnosis or without treatment. Our data suggest that the malignant clone is driven not only by intrinsic properties but also by the interplay with the inflammatory microenvironment. In AML, we showed that an inhibitor of metalloproteinases (TIMP-1) could be considered as a ‘bad actor’ in the leukemic context. TIMP-1 modulates different pathways and we highlighted a cytokine function on AML blasts from AML patients at diagnosis. The survival, migration and proliferation of AML blasts was supported by TIMP-1, delineating a signaling pathway mediated through its receptor CD63 and PI3K/Akt/p21. In parallel, in a mouse model of AML MLL-AF9, we also explored the interaction between bone marrow stromal cells (BMSCs) and leukemic blasts. Through a novel system of co-cultures, we demonstrated the supportive/protective role of BMSCs, as non-adherent cells 'mesenspheres'. In this cross-talk we found a reduction of ROS levels and lipid peroxidation in leukemic blasts co-cultured with BMSCs, in stressed conditions. Importantly, we found also chemo-protective role of mesenspheres on leukemic cells mediated by mitochondria transfer. Surprisingly, this interaction could be explained as transfer of sources of anti-oxidants and nutrients between BMSCs and leukemic cells. Through the entire work, we shed new light on mechanisms and networks in haematological malignancies, such as MF and AML, driving toward novel therapeutic strategy to switch off an inflammatory microenvironment and key players of the malignant niches.
Date
- 2017-05-16
Type
- Doctoral Thesis
- PeerReviewed
Format
- application/pdf
Identifier
urn:nbn:it:unibo-20897
Forte, Dorian (2017) Leukemic Stem/Progenitor Cells and their Microenvironment: The Role of Crucial Inflammatory Factors and Bone Marrow-Derived Mesenspheres, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze biomediche