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

被引：17

作者：

Liso, Arcangelo ^{[1
]}

Castiglione, Filippo ^{[2
]}

Cappuccio, Antonio ^{[2
]}

Stracci, Fabrizio ^{[3
]}

Schlenk, Richard F. ^{[4
]}

Amadori, Sergio ^{[5
]}

Thiede, Christian ^{[6
]}

Schnittger, Susanne ^{[7
]}

Valk, Peter J. M. ^{[8
]}

Doehner, Konstanze ^{[4
]}

Martelli, Massimo F. ^{[9
]}

Schaich, Markus ^{[6
]}

Krauter, Juergen ^{[10
]}

Ganser, Arnold ^{[10
]}

Martelli, Maria P. ^{[9
]}

Bolli, Niccolo ^{[9
]}

Loewenberg, Bob ^{[8
]}

Haferlach, Torsten ^{[7
]}

Ehninger, Gerhard ^{[6
]}

Mandelli, Franco ^{[11
]}

Doehner, Hartmut ^{[4
]}

Michor, Franziska ^{[12
]}

Falini, Brunangelo ^{[9
]}

机构：

[1] Univ Foggia, Inst Hematol, Foggia, Italy

[2] CNR, Ist Applicaz Calcolo M Picone, Rome, Italy

[3] Univ Perugia, Dept Surg Med Spec & Publ Hlth, I-06100 Perugia, Italy

[4] Univ Ulm, Dept Internal Med 3, D-7900 Ulm, Germany

[5] Univ Roma Tor Vergata, Inst Hematol, Rome, Italy

[6] Univ Hosp Carl Gustav Carus, Lab Mol Diagnost, Dresden, Germany

[7] Munich Leukemia Lab, Munich, Germany

[8] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam, Netherlands

[9] Univ Perugia, Inst Hematol, I-06100 Perugia, Italy

[10] Hannover Med Sch, Dept Hematol Hemostasis & Oncol, D-3000 Hannover, Germany

[11] Univ Roma La Sapienza, Inst Hematol, Rome, Italy

[12] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10021 USA

来源：

HAEMATOLOGICA-THE HEMATOLOGY JOURNAL | 2008年 / 93卷 / 08期

关键词：

acute myeloid leukemia; nucleophosmin; mutation;

D O I：

10.3324/haematol.13209

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：1219 / 1226

页数：8

共 47 条

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