title: Stochastic Hypothesis of Transition from Inborn Neutropenia to AML: Interactions of Cell Population Dynamics and Population Genetics.
abstract: We present a stochastic model of driver mutations in the transition from severe congenital neutropenia to myelodysplastic syndrome to acute myeloid leukemia (AML). The model has the form of a multitype branching process. We derive equations for the distributions of the times to consecutive driver mutations and set up simulations involving a range of hypotheses regarding acceleration of the mutation rates in successive mutant clones. Our model reproduces the clinical distribution of times at diagnosis of secondary AML. Surprisingly, within the framework of our assumptions, stochasticity of the mutation process is incapable of explaining the spread of times at diagnosis of AML in this case; it is necessary to additionally assume a wide spread of proliferative parameters among disease cases. This finding is unexpected but generally consistent with the wide heterogeneity of characteristics of human cancers.
authors: Department of Statistics, Rice University Houston, TX, USA ; Department of Bioengineering, Rice University Houston, TX, USA.
authors: Marek
authors: M
authors: Kimmel
authors: Seth
authors: S
authors: Corey
keywords: acute myeloid leukemia; branching process; clonal evolution; driver mutations; myelodysplastic syndrome; severe congenital neutropenia
references: Blood. 2012 May 31;119(22):5071-7
references: 22371884
references: Br J Haematol. 2010 Jul;150(2):196-9
references: 20456363
references: N Engl J Med. 1995 Aug 24;333(8):487-93
references: 7542747
references: Cell. 2011 Mar 4;144(5):646-74
references: 21376230
references: BMC Genomics. 2010 Feb 10;11 Suppl 1:S11
references: 20158868
references: Blood. 2010 Jun 24;115(25):5131-6
references: 20237318
references: Cancer Epidemiol Biomarkers Prev. 2011 Oct;20(10):2048-67
references: 21980013
references: Clin Immunol Immunopathol. 1994 Jan;70(1):10-8
references: 7505211
references: N Engl J Med. 2012 Mar 22;366(12):1090-8
references: 22417201
references: Blood. 2007 Jan 1;109(1):93-9
references: 16985178
references: Bone Marrow Res. 2012;2012:787414
references: 22830032
references: Blood. 2012 May 31;119(22):5063-4
references: 22653952
references: Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18545-50
references: 20876136
references: Br J Haematol. 2012 Aug;158(3):363-9
references: 22624626
references: Haematologica. 2005 Jan;90(1):45-53
references: 15642668
references: Blood. 2010 Mar 25;115(12):2339-47
references: 20103779
references: Nat Rev Cancer. 2004 Mar;4(3):197-205
references: 14993901
references: Nat Med. 1997 Jul;3(7):730-7
references: 9212098
references: Theor Popul Biol. 2010 Nov;78(3):165-72
references: 20600209
references: Blood. 2006 Jun 15;107(12):4628-35
references: 16497969