Neuroglial Regulation of the Haematopoietic Stem Cell Niche in Acute Myeloid Leukaemia Transformation (transfer to Tromsø)
This is an extension of previously approved FOTS9005. The aim of this study is to test the contribution of the neural dysfunction of the bone marrow microenvironment to drive AML, and the therapeutic potential of the reversion of this damage. This project is a continuation of FOTS 7922 and FOTS 9005 to confirm preliminary data with optimized protocols. The expected harmful effect on the animals are mild to transiently severe, only in transplanted mice. The present research will provide with insights into the basic processes that underlie HSC dysfunction and pinpoint a novel therapy against AML. Haematopoiesis has been best characterized in the mouse system and the interaction of the haematopoietic stem cell with its microenvironment can only be studied in vivo, due to the insufficient knowledge of the microenvironment. Number of animals are kept to a minimum (640-estimated 500 in Tromsø) consistent with the obtention of statistically meaningful results. Mice will be used in the most efficient way possible, attempting to obtain the maximum information from each experimental animal. When assays cannot be performed immediately, cells will be cryopreserved whenever possible. Mice will be sacrificed at time points when they will only show haematological symptoms of disease. It is not the goal of this study to analyze terminal stages of disease, but identify the role of the nervous system before severe symptoms develop aiming at uncovering early therapeutic targets against agressive AML.
Etterevaluering
The Norwegian Food Safety Authority must retrospectively assess all severe experiments.
Begrunnelse for etterevalueringen
Despite not having been able to perform the experiments of restoring damaged neuroglial bone marrow components in pre-leukemic mice, we have been able to use an in vivo sympathectomy method, and show that neuroglial damage is an early event in pre-leukemic disease, which contributes to disease progression. Moreover, isolation of Nestin+ cells and frozen bone marrow sections from pre-leukemic NRAS-G12D mice will be useful for other project related to leukemia and the stem cell microenvironment.
Animals with actual severity were animals terminated because of humane endpoint or found dead for unknown reasons. Severity as expected.
We always use in vitro and ex vivo experiments when appropriate, before performing in vivo experiments; transplantation is only performed by experienced researchers; and animals are followed up closely with use of score sheets. As a recent improvement, the conditions are kept sterile starting one week before performing the transplant in this and all our current FOTS.
Animals with actual severity were animals terminated because of humane endpoint or found dead for unknown reasons. Severity as expected.
We always use in vitro and ex vivo experiments when appropriate, before performing in vivo experiments; transplantation is only performed by experienced researchers; and animals are followed up closely with use of score sheets. As a recent improvement, the conditions are kept sterile starting one week before performing the transplant in this and all our current FOTS.