Feedback mechanisms control coexistence in a stem cell model of acute myeloid leukaemia
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Published version
Author(s)
Crowell, HL
MacLean, AL
Stumpf, MP
Type
Journal Article
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.
Date Issued
2016-04-27
Date Acceptance
2016-04-04
Citation
Journal of Theoretical Biology, 2016, 401, pp.43-53
ISSN
1095-8541
Publisher
Elsevier
Start Page
43
End Page
53
Journal / Book Title
Journal of Theoretical Biology
Volume
401
Copyright Statement
© 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Sponsor
Biotechnology and Biological Sciences Research Council (BBSRC)
Grant Number
BB/L023776/1
Subjects
Acute myeloid leukaemia
Cancer
Dynamical systems
Haematopoietic stem cells
Stability analysis
Evolutionary Biology
01 Mathematical Sciences
06 Biological Sciences
08 Information And Computing Sciences
Publication Status
Published