Description

Mathematical Modeling of Heterogeneity, Clonal Selection and Emergence of Resistance in Acute Leukemias

Thomas Stiehl, Anthony D. Ho, Natalia Baran, Christoph Lutz, Anna Marciniak-Czochra

IWR, Heidelberg University, Germany

Recent sequencing studies show that the population of leukemic cells consists of multiple clones. Genetic and phenotypic interdependence of the different clones is complex and so far not well-understood. We propose a range of mathematical models describing evolution of a multiclonal and hierarchical cell population to investigate the impact of mutation and selection on the course of the disease. Model results imply that enhanced self-renewal may be the key mechanism in the clonal selection process. Simulations suggest that quickly proliferating and highly self-renewing cells dominate at primary diagnosis, while the relapse following a therapy-induced remission is triggered mostly by highly self-renewing but slowly proliferating cells. The models allow also to study how mutation rates and phenotypic changes induced by mutations influence the genetic interdependence of the leukemic clones.The results help to understand which phenotypes may be present at different times over the course of disease and how treatment affects the clonal evolution of the disease. Model-based interpretation of clinical data allows estimating parameters that cannot be measured directly. This may have clinical implications for future treatment and follow-up strategies.