| الوصف: |
The bone marrow (BM) microenvironment (the niche) plays a critical role in regulating normal hematopoietic process and is dysregulated in bone and marrow-related malignancies such as Acute Myeloid Leukemia (AML). AML is an aggressive blood cancer affecting the myeloid lineage of the hematopoietic hierarchy, and occurs in mostly individuals of older age. The goal in recent years has been to prolong the survival of these elderly patients, who show morbidity and early induction mortality in the face of intensive treatments. Disease relapse also poses a major hurdle to overcome following the supposed eradication of the leukemic disease, as current disease monitoring strategies used to detect minimal residual disease (MRD) are insufficient and may vary between patients. Many turn to look at the hematopoietic niche for the development of non-cell autonomous AML therapies in the hopes of more targeted and tolerable therapies; however, these strategies focus solely on the elimination of leukemic cells, and remain ignorant to the deterioration of the niche stemming from the disease. As yet, studies on niche cells, including mesenchymal stem cells and their progenies, are riddled with discrepancies and remain challenging to perform as methods used in the field to investigate mesenchymal populations rely primarily on ex vivo assays which are subject to extraneous factors that can lead to biased interpretation. Here, we used an in vitro mesenchymal CFU assay to interrogate the BM niche of AML patients and identify aberrations to the diseased niche throughout progression of the leukemic disease. Our experimental findings showed that while BM adipocyte and osteoblast populations appeared to be equally impaired in AML patients, the reduction in adipogenesis capacity of BM mesenchymal cells seemed to be unique in relapsed patients. We further identified a novel adipogenesis-inducing molecule, Isoginkgetin, that can successfully correct this deficiency in AML BM-MSCs and promote BM adipogenesis in vivo. Thesis Master of Health Sciences (MSc) |