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 outcomesdisease 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.ematopoiesis is the intricate process that provides the vast diversity of cells found in the blood and immune system of vertebrate organisms. To generate great numbers of very different cellsranging from erythrocytes to highly specialized lymphocytes-a delicate balance of activity of transcriptional programs and hematopoietic growth factors is required (1). Within this system, hematopoietic stem cells (HSCs) give rise to (lymphoid and myeloid) progenitors, which in turn through further differentiation steps yield the panoply of cells found in the blood (2). Given the complexity of the hematopoietic system it is remarkable how robustly this process works in general.The cellular and molecular processes involved in healthy hematopoiesis must be disrupted in disease (3). There is however solid evidence that disease processes operate in parallel to the normal hematopoietic system. Thus, a branch of the hematopoietic system will propagate deficient cells and generate the ensuing pathology, but other cells of the system will continue to operate alongside (4-7). This is, of course, akin to problems encountered in ecology. Based on this analogy we here attempt to understand the interplay between the healthy and chronic myeloid leukemia (CML) systems. This is a particularly helpful perspective if interactions between healthy and diseased cell types can affect the disease progression, as is now widely believed.Interactions will include shared reliance on nutrients, cofactors, and physiologi...

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