In some patients with myeloproliferative neoplasms (MPN), two genetic mutations are often found: JAK2 V617F and one in the TET2 gene. Whether one mutation is present influences how the other subsequent mutation will affect the regulation of gene expression. In other words, when a patient carries both mutations, the order of when they first arose has been shown to influence disease progression and prognosis. We propose a nonlinear ordinary differential equation, the Moran process, and Markov chain models to explain the non-additive and non-commutative mutation effects on recent clinical observations of gene expression patterns, proportions of cells with different mutations, and ages at diagnosis of MPN. Combined, these observations are used to shape our modeling framework. Our key proposal is that bistability in gene expression provides a natural explanation for many observed order-of-mutation effects. We also propose potential experimental measurements that can be used to confirm or refute predictions of our models.

在一些骨髓增生性肿瘤 (MPN) 患者中，经常发现两种基因突变：JAK2 V617F 和 TET2 基因中的一种。一种突变是否存在会影响另一种后续突变如何影响基因表达的调节。换句话说，当患者携带两种突变时，它们首次出现的顺序已被证明会影响疾病进展和预后。我们提出了非线性常微分方程、莫兰过程和马尔可夫链模型来解释非加性和非交换突变对近期临床观察的基因表达模式、具有不同突变的细胞比例以及 MPN 诊断年龄的影响。这些观察结果结合起来用于塑造我们的建模框架。我们的主要建议是，基因表达的双稳定性为许多观察到的突变顺序效应提供了自然的解释。我们还提出了潜在的实验测量，可用于证实或反驳我们模型的预测。