Liso Arcangelo, Castiglione Filippo, Cappuccio Antonio, Stracci Fabrizio, Schlenk Richard F, Amadori Sergio, Thiede Christian, Schnittger Susanne, Valk Peter J M, Döhner Konstanze, Martelli Massimo F, Schaich Markus, Krauter Jürgen, Ganser Arnold, Martelli Maria P, Bolli Niccolò, Löwenberg Bob, Haferlach Torsten, Ehninger Gerhard, Mandelli Franco, Döhner Hartmut, Michor Franziska, Falini Brunangelo
Institute of Hematology, University of Foggia, Foggia, Italy.
Haematologica. 2008 Aug;93(8):1219-26. doi: 10.3324/haematol.13209. Epub 2008 Jul 4.
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.
伴有NPM1基因突变及核磷蛋白异常胞质表达的急性髓系白血病（NPMc(+)急性髓系白血病）具有独特的生物学和临床特征。然而，核磷蛋白突变体致癌潜能的实验证据仍然缺乏，并且尚不清楚其他遗传病变，例如FLT3内部串联重复，是否在急性髓系白血病发生过程中与NPM1突变协同作用。对年龄特异性发病率进行分析，并结合急性髓系白血病流行病学的数学模型，有助于揭示引发白血病所需的遗传事件数量。我们收集了来自德国、荷兰和意大利五个欧洲中心的急性髓系白血病患者的诊断年龄数据，并确定了每个国家伴有NPM1突变的急性髓系白血病（共1444例）的年龄特异性发病率。代表每年年龄特异性诊断率的曲线的线性回归显示，在双对数尺度上，斜率约为4，较为相似。然后，我们采用先前设计的造血肿瘤发生数学模型来分析伴有NPM1突变的急性髓系白血病的年龄发病率，发现单突变模型可以解释这种白血病实体的发病率曲线。该模型符合以下假设：NPMc(+)急性髓系白血病起源于野生型NPM1等位基因单倍剂量不足的NPM1突变。
