title: Clonal selection and therapy resistance in acute leukaemias: mathematical modelling explains different proliferation patterns at diagnosis and relapse.
abstract: Recent experimental evidence suggests that acute myeloid leukaemias may originate from multiple clones of malignant cells. Nevertheless, it is not known how the observed clones may differ with respect to cell properties, such as proliferation and self-renewal. There are scarcely any data on how these cell properties change due to chemotherapy and relapse. We propose a new mathematical model to investigate the impact of cell properties on the multi-clonal composition of leukaemias. Model results imply that enhanced self-renewal may be a key mechanism in the clonal selection process. Simulations suggest that fast proliferating and highly self-renewing cells dominate at primary diagnosis, while relapse following therapy-induced remission is triggered mostly by highly self-renewing but slowly proliferating cells. Comparison of simulation results to patient data demonstrates that the proposed model is consistent with clinically observed dynamics based on a clonal selection process.
authors.affiliation: Institute of Applied Mathematics, BIOQUANT and IWR, Im Neuenheimer Feld 294, University of Heidelberg, , 69120 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stiehl
authors.forename: Natalia
authors.initials: N
authors.lastname: Baran
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.forename: Anna
authors.initials: A
authors.lastname: Marciniak-Czochra
mesh_terms: D000208:Acute Disease; D000818:Animals; D049109:Cell Proliferation; D060966:Clonal Selection, Antigen-Mediated; D006801:Humans; D007938:Leukemia / Q000175:diagnosis / Q000276:immunology / Q000378:metabolism; D008954:Models, Biological; D012008:Recurrence
keywords: cancer stem cells; clonal evolution; leukaemia; mathematical models; selection process