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Front Oncol. 2013 Apr 29;3:89. doi: 10.3389/fonc.2013.00089. eCollection 2013.

Stochastic Hypothesis of Transition from Inborn Neutropenia to AML: Interactions of Cell Population Dynamics and Population Genetics.

Author information

  • 1Department of Statistics, Rice University Houston, TX, USA ; Department of Bioengineering, Rice University Houston, TX, USA.

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.

KEYWORDS:

acute myeloid leukemia; branching process; clonal evolution; driver mutations; myelodysplastic syndrome; severe congenital neutropenia

PMID:
23641360
[PubMed]
PMCID:
PMC3638131
Free PMC Article
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