Inhibiting Matrix Metalloproteinases Hinders Acute Myeloid Leukaemia And Prevents Healthy Stem Cell Loss

Haematopoietic stem cells (HSCs), despite being very rare (<0.015% of bone marrow haematopoietic cells), maintain the turnover of all blood cells through a balance of quiescence, self-renewal and differentiation. Disruption of HSCs function and of the bone marrow (BM) microenvironment are key aspects of Acute Myeloid Leukaemia (AML). AML develops in adults and symptoms arise due to the loss of healthy haematopoietic cells. It is unknown exactly what factors contribute to this although it is clear that there is a progressive loss of BM HSCs in this disease. One hypothesis is that HSCs are pushed out of the BM niche by competing leukaemic blasts. To explore this, we used intravital 2-photon confocal microscopy in a live mouse model of leukaemia which allows us to visualise the dynamics of healthy haematopoietc cells at various stages of the disease. We monitored the development of extramedullary haematopoiesis (EMH) during AML growth and tested the function of HSCs found in these alternative sites to determine whether EMH acts as an alternative mechanism of blood cell maintenance in response to AML. Furthermore, we investigated the influence of an extracellular matrix metalloproteinase inhibitor, Prinomastat, on the loss of HSCs in this model. Prinomastat has been studied extensively in solid organ cancers as it has been shown capable of inhibiting cancer metastasis. In this study, we examined whether it might have a function in preventing the loss of HSCs from the bone during leukaemia infiltration.