Zhang Jie, Fleischman Angela G, Wodarz Dominik, Komarova Natalia L
Department of Mathematics, USA.
Division of Hematology/Oncology, USA.
J Theor Biol. 2017 Jul 21;425:43-52. doi: 10.1016/j.jtbi.2017.05.012. Epub 2017 May 10.
Myeloproliferative neoplasm (MPN) is a hematologic malignancy characterized by the clonal outgrowth of hematopoietic cells with a somatically acquired mutation most commonly in JAK2 (JAK2). This mutation endows upon myeloid progenitors cytokine independent growth and consequently leads to excessive production of myeloid lineage cells. It has been previously suggested that inflammation may play a role in the clonal evolution of JAK2 mutants. In particular, it is possible that one or more cellular kinetic parameters of hematopoietic stem cells (HSCs) are affected by inflammation, such as division or death rates of cells, and the probability of HSC differentiation. This suggests a mechanism that can steer the outcome of the cellular competition in favor of the mutants, initiating the disease. In this paper we create a number of mathematical evolutionary models, from very abstract to more concrete, that describe cellular competition in the context of inflammation. It is possible to build a model axiomatically, where only very general assumptions are imposed on the modeling components and no arbitrary (and generally unknown) functional forms are used, and still generate a set of testable predictions. In particular, we show that, if HSC death is negligible, the evolutionary advantage of mutant cells can only be conferred by an increase in differentiation probability of HSCs in the presence of inflammation, and if death plays a significant role in the dynamics, an additional mechanism may be an increase of HSC's division-to-death ratio in the presence of inflammation. Further, we show that in the presence of inflammation, the wild type cell population is predicted to shrink under inflammation (even in the absence of mutants). Finally, it turns out that if only the differentiation probability is affected by the inflammation, then the resulting steady state population of wild type cells will contain a relatively smaller percentage of HSCs under inflammation. If the division-to-death rate is also affected, then the percentage of HSCs under inflammation can either decrease or increase, depending on other parameters.
骨髓增殖性肿瘤（MPN）是一种血液系统恶性肿瘤，其特征是造血细胞发生克隆性增殖，并伴有体细胞获得性突变，最常见于JAK2基因（JAK2）。这种突变赋予髓系祖细胞不依赖细胞因子的生长能力，从而导致髓系细胞过度生成。此前有研究表明，炎症可能在JAK2突变体的克隆进化中发挥作用。特别是，造血干细胞（HSC）的一个或多个细胞动力学参数可能受到炎症影响，如细胞的分裂或死亡率，以及HSC分化的概率。这提示了一种机制，可使细胞竞争结果有利于突变体，从而引发疾病。在本文中，我们创建了一系列数学进化模型，从非常抽象到较为具体，用于描述炎症背景下的细胞竞争。可以通过公理法构建模型，即仅对建模组件施加非常一般的假设，不使用任意（且通常未知）的函数形式，仍然能够生成一组可检验的预测。特别是，我们表明，如果HSC死亡可忽略不计，突变细胞的进化优势只能通过炎症存在时HSC分化概率的增加来赋予；如果死亡在动力学中起重要作用，另一种机制可能是炎症存在时HSC分裂与死亡比率的增加。此外，我们表明在炎症存在的情况下，野生型细胞群体预计会在炎症下缩小（即使在没有突变体的情况下）。最后，结果表明，如果只有分化概率受炎症影响，那么炎症下野生型细胞的最终稳态群体将包含相对较小比例的HSC。如果分裂与死亡率也受影响，那么炎症下HSC的比例可能会降低或增加，这取决于其他参数。
