Mathematical modeling offers the opportunity to test hypothesis concerning Myeloproliferative emergence and development. We tested different mathematical models based on a training cohort (n=264 patients) (Registre de la c\^ote d'Or) to determine the emergence and evolution times before JAK2V617F classical Myeloproliferative disorders (respectively Polycythemia Vera and Essential Thrombocytemia) are diagnosed. We dissected the time before diagnosis as two main periods: the time from embryonic development for the JAK2V617F mutation to occur, not disappear and enter in proliferation, and a second time corresponding to the expansion of the clonal population until diagnosis. We demonstrate using progressively complexified models that the rate of active mutation occurrence is not constant and doesn't just rely on individual variability, but rather increases with age and takes a median time of 63.1+/-13 years. A contrario, the expansion time can be considered as constant: 8.8 years once the mutation has emerged. Results were validated in an external cohort (national FIMBANK Cohort, n=1248 patients). Analyzing JAK2V617F Essential Thrombocytema versus Polycythemia Vera, we noticed that the first period of time (rate of active homozygous mutation occurrence) for PV takes approximatively 1.5 years more than for ET to develop when the expansion time was quasi-similar. In conclusion, our multi-step approach and the ultimate time-dependent model of MPN emergence and development demonstrates that the emergence of a JAK2V617F mutation should be linked to an aging mechanism, and indicates a 8-9 years period of time to develop a full MPN.

翻译：数学模型为检验有关骨髓增殖性肿瘤发生与发展的假说提供了可能。我们基于一个训练队列（n=264例患者）（科多尔省登记库）测试了不同的数学模型，以确定在JAK2V617F经典骨髓增殖性肿瘤（分别为真性红细胞增多症和原发性血小板增多症）被诊断之前，其发生与演进所需的时间。我们将诊断前的时间解析为两个主要阶段：第一阶段是从胚胎发育开始，JAK2V617F突变发生、未消失并进入增殖状态所需的时间；第二阶段对应于克隆群体扩增直至诊断的时间。我们通过逐步复杂化的模型证明，活性突变发生的速率并非恒定，也不仅仅依赖于个体差异，而是随着年龄增长而增加，其中位时间约为63.1±13年。相反，扩增时间可被视为恒定：一旦突变发生，约为8.8年。这些结果在一个外部队列（国家FIMBANK队列，n=1248例患者）中得到了验证。通过分析JAK2V617F原发性血小板增多症与真性红细胞增多症，我们注意到，在扩增时间几乎相似的情况下，PV所需的第一阶段（活性纯合突变发生速率）比ET多发展约1.5年。总之，我们的多步骤方法以及最终的MPN发生与发展的时间依赖性模型表明，JAK2V617F突变的发生应与衰老机制相关，并指出发展成完整MPN需要8-9年的时间。