Colijn Caroline, Mackey Michael C
Department of Mathematics and Centre for Nonlinear Dynamics, McGill University, 3655 Promenade Sir William Osler, Montreal, Que., Canada H3G 1Y6.
J Theor Biol. 2005 Nov 21;237(2):117-32. doi: 10.1016/j.jtbi.2005.03.033. Epub 2005 Jun 21.
Periodic chronic myelogenous leukemia (PCML) is an interesting dynamical disease of the hematopoietic system in which oscillating levels of circulating leukocytes, platelets and/or reticulocytes are observed. Typically all of these three differentiated cell types have the same oscillation period, but the relation of the oscillation mean and amplitude to the normal levels is variable. Given the appearance of the abnormal Philadelphia chromosome in all of the nucleated progeny of the hematopoietic stem cells (HSCs), the most parsimonious conclusion is that chronic myelogenous leukemia, and its periodic variant, arise from derangements partially involving the dynamics of the stem cells. Here, we have synthesized several previous mathematical models of HSC dynamics, and models for the regulation of neutrophils, platelets and erythrocytes into a comprehensive model for the regulation of the hematopoietic system. Based on estimates of parameters for a typical normal human, we have systematically explored the changes in some of these parameters necessary to account for the quantitative data on leukocyte, platelet and reticulocyte cycling in 11 patients with PCML. Our results indicate that the critical model parameter changes required to simulate the PCML patient data are an increase in the amplification in the leukocyte line, an increase in the differentiation rate from the stem cell compartment into the leukocyte line, and the rate of apoptosis in the stem cell compartment. Our model system is particularly sensitive to changes in stem cell apoptosis rates, suggesting that changes in the numbers of proliferating stem cells may be important in generating PCML.
周期性慢性粒细胞白血病（PCML）是造血系统中一种有趣的动态疾病，在该疾病中可观察到循环白细胞、血小板和/或网织红细胞水平的振荡。通常，这三种分化细胞类型的振荡周期相同，但振荡平均值和幅度与正常水平的关系是可变的。鉴于在造血干细胞（HSC）的所有有核后代中都出现了异常的费城染色体，最简洁的结论是慢性粒细胞白血病及其周期性变体源于部分涉及干细胞动力学紊乱。在这里，我们将之前几个关于HSC动力学的数学模型以及中性粒细胞、血小板和红细胞调节模型整合为一个造血系统调节的综合模型。基于对典型正常人类参数的估计，我们系统地探索了一些参数的变化，这些变化是解释11例PCML患者白细胞、血小板和网织红细胞循环定量数据所必需的。我们的结果表明，模拟PCML患者数据所需的关键模型参数变化是白细胞系扩增增加、从干细胞区室向白细胞系的分化率增加以及干细胞区室的凋亡率增加。我们的模型系统对干细胞凋亡率的变化特别敏感，这表明增殖干细胞数量的变化可能对PCML的发生很重要。
