A mathematical model of hematopoiesis - I. Periodic chronic myelogenous leukemia
A mathematical model of hematopoiesis - I. Periodic chronic myelogenous leukemia
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DOI：
10.1016/j.jtbi.2005.03.033
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发表时间：
2005-11-21
影响因子：
2
通讯作者：
Mackey, MC
中科院分区：
文献类型：
--
作者：
Colijn, C;Mackey, MC
周期性慢性髓细胞性白血病（PCML）是一种造血系统动力学疾病，其中观察到循环白细胞、血小板和/或网织红细胞的振荡水平。通常，所有这三种分化的细胞类型具有相同的振荡周期，但振荡平均值和振幅与正常水平的关系是可变的。鉴于在所有造血干细胞（HSC）的有核后代中出现异常费城染色体，最简单的结论是慢性髓细胞性白血病及其周期性变体是由部分涉及干细胞动力学的紊乱引起的。在这里，我们已经合成了几个以前的HSC动力学的数学模型，和中性粒细胞，血小板和红细胞的调节模型到一个全面的造血系统的调节模型。基于一个典型的正常人的参数的估计，我们系统地探讨了这些参数的变化，这些参数的变化需要占白细胞，血小板和网织红细胞循环在11例PCML患者的定量数据。我们的研究结果表明，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的增加，从干细胞隔室到白细胞系的分化率的增加，以及干细胞隔室中的细胞凋亡率。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在产生PCML中可能是重要的。(c)2005爱思唯尔有限公司保留所有权利。
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. (c) 2005 Elsevier Ltd. All rights reserved.