title: Emergence of heterogeneity in acute leukemias.
abstract: Leukemias are malignant proliferative disorders of the blood forming system. Sequencing studies demonstrate that the leukemic cell population consists of multiple clones. The genetic relationship between the different clones, referred to as the clonal hierarchy, shows high interindividual variability. So far, the source of this heterogeneity and its clinical relevance remain unknown. We propose a mathematical model to study the emergence and evolution of clonal heterogeneity in acute leukemias. The model allows linking properties of leukemic clones in terms of self-renewal and proliferation rates to the structure of the clonal hierarchy.
  
  
  
  Computer simulations imply that the self-renewal potential of the first emerging leukemic clone has a major impact on the total number of leukemic clones and on the structure of their hierarchy. With increasing depth of the clonal hierarchy the self-renewal of leukemic clones increases, whereas the proliferation rates do not change significantly. The emergence of deep clonal hierarchies is a complex process that is facilitated by a cooperativity of different mutations.
  
  
  
  Comparison of patient data and simulation results suggests that the self-renewal of leukemic clones increases with the emergence of clonal heterogeneity. The structure of the clonal hierarchy may serve as a marker for patient prognosis.
  
  
  
  This article was reviewed by Marek Kimmel, Tommaso Lorenzi and Tomasz Lipniacki.
authors.affiliation: Institute of Applied Mathematics, Heidelberg University, Im Neuenheimer Feld 205, Heidelberg, 69120, Germany. Thomas.Stiehl@iwr.uni-heidelberg.de.|Interdisciplinary Center for Scientific Computing, Heidelberg University, Im Neuenheimer Feld 205, Heidelberg, 69120, Germany. Thomas.Stiehl@iwr.uni-heidelberg.de.|Bioquant Center, Heidelberg University, Im Neuenheimer Feld 297, Heidelberg, 69120, Germany. Thomas.Stiehl@iwr.uni-heidelberg.de.
authors.forename: Thomas
authors.identifier: 0000-0001-9686-9197
authors.initials: T
authors.lastname: Stiehl
authors.affiliation: Department of Medicine V, Heidelberg University, Im Neuenheimer Feld 410, Heidelberg, 69120, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lutz
authors.affiliation: Institute of Applied Mathematics, Heidelberg University, Im Neuenheimer Feld 205, Heidelberg, 69120, Germany.|Interdisciplinary Center for Scientific Computing, Heidelberg University, Im Neuenheimer Feld 205, Heidelberg, 69120, Germany.|Bioquant Center, Heidelberg University, Im Neuenheimer Feld 297, Heidelberg, 69120, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Marciniak-Czochra
mesh_terms: D000208:Acute Disease; D002999:Clone Cells; D003198:Computer Simulation; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D011110:Polymorphism, Genetic
keywords: Acute leukemia; Clonal evolution; Clonal hierarchy; Heterogeneity; Mathematical modeling; Mutation; Patient prognosis; Self-renewal