Does ageing foster transformation to Acute Myeloid Leukaemia? Study of mice cohort bearing haematopoietic malignancy burden, and the effects of ageing on leukaemia progression and on the bone marrow microenvironment
Haematopoiesis originates from haematopoietic stem cells (HSC), whose functions and maintenance are regulated in both cell- and non-cell autonomous ways. The surroundings generate a specific niche or microenvironment, in which HSC nest, that also influences their self-renewal characteristics. The cellular players in the haematopoietic niche include vascular beds, mature blood cells, and various cells of stromal and neural origin. Stromal cells are regulated by the sympathetic nervous system, which is responsible for fluctuation of the HSC into the bloodstream in a circadian manner. It is becoming increasingly clear, that the neural regulation has more pronounced effects on HSC. For instance, in diseases such as myeloproliferative neoplasms, HSC-derived inflammation together with neuropathy induce apoptosis in stromal compartment, which subsequently allows expansion of mutant HSC (Arranz et al., 2014). The niche is also important in leukaemia, with malignant cells reprogramming certain cellular niche components. Ageing of the haematopoietic system is also heavily influencing HSC abilities, causing immunosenescence and clonal abnormalities that can be considered as pre-leukaemic lesions. The age-related changes in HSC niche are scarcely investigated, particularly in the context of malignancies. In this study, potential leukaemic transformation was studied throughout ageing in mice, and the same animals were also monitored for changes in the microenvironment of the bone marrow. Investigated mice presented a haematopoietic phenotype typical for development of haematopoietic malignancy, and we show that this phenotype is remarkably aggravated in old mice. Changes in myeloid cells and HSC, with severe extramedullary haematopoiesis may indicate leukaemic transformation that should be followed up in future work. Mesenchymal cells were found to undergo similar reduction in healthy and leukaemic mice in the old age. Our data points to CD90-expressing mesenchymal cells as a niche component that should be considered in the future. Augmented inflammatory status related to interleukin 1 was detected in those individuals, but regulation through interleukin 1 receptor expression seems to be absent in old transgenic mice. In summary, the data presented here seems to point to ageing as an important factor influencing invasiveness in haematopoietic malignancies.
PublisherUiT Norges arktiske universitet
UiT The Arctic University of Norway
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