title: A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1).
abstract: Acute myeloid leukemia with mutated NPM1 gene and aberrant cytoplasmic expression of nucleophosmin (NPMc(+) acute myeloid leukemia) shows distinctive biological and clinical features. Experimental evidence of the oncogenic potential of the nucleophosmin mutant is, however, still lacking, and it is unclear whether other genetic lesion(s), e.g. FLT3 internal tandem duplication, cooperate with NPM1 mutations in acute myeloid leukemia development. An analysis of age-specific incidence, together with mathematical modeling of acute myeloid leukemia epidemiology, can help to uncover the number of genetic events needed to cause leukemia. We collected data on age at diagnosis of acute myeloid leukemia patients from five European Centers in Germany, The Netherlands and Italy, and determined the age-specific incidence of AML with mutated NPM1 (a total of 1,444 cases) for each country. Linear regression of the curves representing age-specific rates of diagnosis per year showed similar slopes of about 4 on a double logarithmic scale. We then adapted a previously designed mathematical model of hematopoietic tumorigenesis to analyze the age incidence of acute myeloid leukemia with mutated NPM1 and found that a one-mutation model can explain the incidence curve of this leukemia entity. This model fits with the hypothesis that NPMc(+) acute myeloid leukemia arises from an NPM1 mutation with haploinsufficiency of the wild-type NPM1 allele.
authors.affiliation: Institute of Hematology, University of Foggia, Foggia, Italy. a.liso@medicina.unifg.it
authors.forename: Arcangelo
authors.initials: A
authors.lastname: Liso
authors.forename: Filippo
authors.initials: F
authors.lastname: Castiglione
authors.forename: Antonio
authors.initials: A
authors.lastname: Cappuccio
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Stracci
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Massimo F
authors.initials: MF
authors.lastname: Martelli
authors.forename: Markus
authors.initials: M
authors.lastname: Schaich
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Maria P
authors.initials: MP
authors.lastname: Martelli
authors.forename: Niccolò
authors.initials: N
authors.lastname: Bolli
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.forename: Franco
authors.initials: F
authors.lastname: Mandelli
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
authors.forename: Brunangelo
authors.initials: B
authors.lastname: Falini
mesh_terms: D000328:Adult; D017668:Age of Onset; D005060:Europe; D020440:Gene Duplication; D005858:Germany; D006801:Humans; D015994:Incidence; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology / Q000235:genetics*; D008875:Middle Aged; D008957:Models, Genetic; D008962:Models, Theoretical; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D012042:Registries; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3