A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1).
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.
Liso
Arcangelo
A
Institute of Hematology, University of Foggia, Foggia, Italy. a.liso@medicina.unifg.it
Castiglione
Filippo
F
Cappuccio
Antonio
A
Stracci
Fabrizio
F
Schlenk
Richard F
RF
Amadori
Sergio
S
Thiede
Christian
C
Schnittger
Susanne
S
Valk
Peter J M
PJ
Döhner
Konstanze
K
Martelli
Massimo F
MF
Schaich
Markus
M
Krauter
Jürgen
J
Ganser
Arnold
A
Martelli
Maria P
MP
Bolli
Niccolò
N
Löwenberg
Bob
B
Haferlach
Torsten
T
Ehninger
Gerhard
G
Mandelli
Franco
F
Döhner
Hartmut
H
Michor
Franziska
F
Falini
Brunangelo
B
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
C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3