Population dynamics of normal and leukaemia stem cells in the haematopoietic stem cell niche show distinct regimes where leukaemia will be controlled.
Haematopoietic stem cells (HSCs) are responsible for maintaining immune cells, red blood cells and platelets throughout life. HSCs must be located in their ecological niche (the bone marrow) to function correctly, that is, to regenerate themselves and their progeny; the latter eventually exit the bone marrow and enter circulation. We propose that cells with oncogenic potential-cancer/leukaemia stem cells (LSC)-and their progeny will also occupy this niche. Mathematical models, which describe the dynamics of HSCs, LSCs and their progeny allow investigation into the conditions necessary for defeating a malignant invasion of the niche. Two such models are developed and analysed here. To characterize their behaviour, we use an inferential framework that allows us to study regions in parameter space that give rise to desired behaviour together with an assessment of the robustness of the dynamics. Using this approach, we map out conditions under which HSCs can outcompete LSCs. In therapeutic applications, we clearly want to drive haematopoiesis into such regimes and the current analysis provide some guidance as to how we can identify new therapeutic targets. Our results suggest that maintaining a viable population of HSCs and their progenies in the niche may often already be nearly sufficient to eradicate LSCs from the system.
Theoretical Systems Biology, Division of Molecular Biosciences, Imperial College London, Sir Ernst Chain Building, London SW7 2AZ, UK.
Adam L
AL
MacLean
Cristina
C
Lo Celso
Michael P H
MP
Stumpf
D001499:Bayes Theorem; D001854:Bone Marrow Cells / Q000166:cytology*; D060833:Cellular Microenvironment; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007938:Leukemia / Q000503:physiopathology*; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000166:cytology*