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A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1)

¹ Institute of Hematology, University of Foggia, Foggia, Italy;
² Istituto Applicazioni del Calcolo "M. Picone", Consiglio Nazionale delle Ricerche (CNR), Rome, Italy;
³ Dept. Surg. Med. Spec. and Public Health, University of Perugia, Italy;
⁴ Department of Internal Medicine III, University of Ulm, Ulm, Germany;
⁵ Institute of Hematology, University of Tor Vergata, Rome, Italy;
⁶ Laboratory for Molecular Diagnostics, University Hospital Carl Gustav Carus, Dresden, Germany;
⁷ MLL–Munich Leukemia Laboratory, Munich, Germany;
⁸ Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
⁹ Institute of Hematology, University of Perugia, Perugia, Italy;
¹⁰ Department of Hematology, Hemostasis and Oncology, Hannover Medical School, Hannover, Germany;
¹¹ Institute of Hematology, University "La Sapienza", Rome, Italy;
¹² Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA

Correspondence: Arcangelo Liso, Institute of Hematology, University of Foggia, Foggia, Italy. E-mail:a.liso{at}medicina.unifg.it or Brunangelo Falini, Institute of Hematology, University of Perugia, Italy. E-mail:faliniem{at}unipg.it

ABSTRACT

Acute myeloid leukemia (AML) with mutated NPM1 gene and aberrant cytoplasmic expression of nucleophosmin (NPMc⁺ AML) 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 (ITD), cooperate with NPM1 mutations in AML development. An analysis of age-specific incidence, together with mathematical modeling of AML epidemiology, can help to uncover the number of genetic events needed to cause leukemia. We collected data on age at diagnosis of AML 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 AML 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⁺ AML arises from an NPM1 mutation with haploinsufficiency of the wild-type NPM1 allele.

Key words: acute myeloid leukemia, nucleophosmin, mutation.