title: Feedback mechanisms control coexistence in a stem cell model of acute myeloid leukaemia.
abstract: Haematopoietic stem cell dynamics regulate healthy blood cell production and are disrupted during leukaemia. Competition models of cellular species help to elucidate stem cell dynamics in the bone marrow microenvironment (or niche), and to determine how these dynamics impact leukaemia progression. Here we develop two models that target acute myeloid leukaemia with particular focus on the mechanisms that control proliferation via feedback signalling. It is within regions of parameter space permissive of coexistence that the effects of competition are most subtle and the clinical outcome least certain. Steady state and linear stability analyses identify parameter regions that allow for coexistence to occur, and allow us to characterise behaviour near critical points. Where analytical expressions are no longer informative, we proceed statistically and sample parameter space over a coexistence region. We find that the rates of proliferation and differentiation of healthy progenitors exert key control over coexistence. We also show that inclusion of a regulatory feedback onto progenitor cells promotes healthy haematopoiesis at the expense of leukaemia, and that - somewhat paradoxically - within the coexistence region feedback increases the sensitivity of the system to dominance by one lineage over another.
authors.affiliation: Theoretical Systems Biology, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Helena L
authors.initials: HL
authors.lastname: Crowell
authors.affiliation: Theoretical Systems Biology, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Adam L
authors.initials: AL
authors.lastname: MacLean
authors.affiliation: Theoretical Systems Biology, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK. Electronic address: m.stumpf@imperial.ac.uk.
authors.forename: Michael P H
authors.initials: MP
authors.lastname: Stumpf
mesh_terms: D001854:Bone Marrow Cells; D002454:Cell Differentiation; D019070:Cell Lineage / Q000502:physiology; D049109:Cell Proliferation; D025461:Feedback, Physiological / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008954:Models, Biological; D055153:Stem Cell Niche
keywords: Acute myeloid leukaemia; Cancer; Dynamical systems; Haematopoietic stem cells; Stability analysis