CCBIO seminar: Lorena Arranz
Neuroglial dysregulation of the haematopoietic stem cell niche in myeloid leukaemias
Stem Cell Aging and Cancer Research Group, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø
Acute myeloid leukaemia (AML) is the most common form of acute leukaemia occurring in adults, its incidence increases with age and the prognosis for the older patient remains bleak. Overcoming these problems will require improved understanding of AML. Oncogenes frequently mutated in human AML that confer a survival advantage to the haematopoietic stem cell (HSC), such as RAS and FLT3, are only able to induce myeloproliferative neoplasms (MPN) in mouse models. This indicates that these lesions are insufficient to cause AML and suggests participation of other factors. Until recently the focus has been on the search for additional genetic mutationswith little consideration of the bone marrow (BM) HSC niche. The latter has a significant influence on haemopoiesis under healthy conditions. Further, our recent work uncovered an unprecedented role for the BM HSC niche in MPN pathological conditions (Arranz et al. Nature, 2014, 512:78). We specifically showed the role in disease progression of the neuroglial components and mesenchymal stem cells (MSC) in the BM with the JAK2-V617Fmutation, which improves HSC survival. As an early event in the course of polycythemia vera, the mutant JAK2-V617F+ HSC promotes inflammation through IL-1β production. This leads to damage of BM sympathetic fibres and covering Schwann cells, causing MSC apoptosis. Loss of the inhibitory regulation exerted by these BM niche components then allows uncontrolled expansion of mutant JAK2-V617F+ HSC and worsens the inflammatory environment. The pathogenic role of these changes was demonstrated by prevention of further MSC apoptosis and inflammation through enhancement of adrenergic activity using a β3-adrenergic agonist. This treatment blocked disease progression in mice and will soon be confirmed in patients with MPN.
Currently, the primary aims of the recently established research group are to test the potential role of the BM niche in leukaemic transformation and to study the importance of this to human AML. Our recent research will be presented, followed by a glimpse over the research group, our ongoing research and future directions.
Chairperson: Bjørn Tore Gjertsen, CCBIO