title: The ecology in the hematopoietic stem cell niche determines the clinical outcome in chronic myeloid leukemia.
abstract: Chronic myeloid leukemia (CML) is a blood disease that disrupts normal function of the hematopoietic system. Despite the great progress made in terms of molecular therapies for CML, there remain large gaps in our understanding. By comparing mathematical models that describe CML progression and etiology we sought to identify those models that provide the best description of disease dynamics and their underlying mechanisms. Data for two clinical outcomes--disease remission or relapse--are considered, and we investigate these using Bayesian inference techniques throughout. We find that it is not possible to choose between the models based on fits to the data alone; however, by studying model predictions we can discard models that fail to take niche effects into account. More detailed analysis of the remaining models reveals mechanistic differences: for one model, leukemia stem cell dynamics determine the disease outcome; and for the other model disease progression is determined at the stage of progenitor cells, in particular by differences in progenitor death rates. This analysis also reveals distinct transient dynamics that will be experimentally accessible, but are currently at the limits of what is possible to measure. To resolve these differences we need to be able to probe the hematopoietic stem cell niche directly. Our analysis highlights the importance of further mapping of the bone marrow hematopoietic niche microenvironment as the "ecological" interactions between cells in this niche appear to be intricately linked to disease outcome.
authors.affiliation: Theoretical Systems Biology, Division of Molecular Biosciences, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Adam L
authors.initials: AL
authors.lastname: MacLean
authors.forename: Sarah
authors.initials: S
authors.lastname: Filippi
authors.forename: Michael P H
authors.initials: MP
authors.lastname: Stumpf
mesh_terms: D001499:Bayes Theorem; D018450:Disease Progression; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology / Q000503:physiopathology*; D008954:Models, Biological; D055153:Stem Cell Niche / Q000502:physiology*; D059016:Tumor Microenvironment / Q000502:physiology*
keywords: cancer progression; competition; model selection; niche dynamics