Grossman Z
EMBO J. 1986 Apr;5(4):671-7. doi: 10.1002/j.1460-2075.1986.tb04266.x.
The mechanisms responsible for the massive hyperplasia and for the blastic crisis in chronic myelocytic leukemia are poorly understood. The most generally accepted hypothesis proposes that this progression is due to the development of genetic instability in the leukemic cells. In particular, the two phases of the disease are believed to reflect different, discrete genetic events. Such events remain undefined as yet, and the causal significance of observed genetic aberrations is not clear. An alternative hypothesis is presented here. It is assumed that the feedback interactions adjust the relative probabilities of maturation and replication of the 'committed' as well as the pluripotent cells, and further that mitotic cells at all stages possess considerable phenotypic adaptability; in particular their self-renewal capacity can vary in response to changes in the cellular composition of the tissue even within a conventionally defined compartment. On this basis, it is shown that chronic leukemia can arise and evolve into the blastic crisis from a progressive decline in a single clonal characteristic--inducibility to maturation. It is shown, with the help of mathematical considerations, how an initial hereditable event in an early hemopoietic cell can cause a disturbance of the tissue which feeds back onto the individual members of the clone, resulting in a cascade of dynamic changes which can lead to blast cell dominance.
慢性粒细胞白血病中导致大量细胞增生和原始细胞危象的机制目前还了解甚少。最被广泛接受的假说是，这种病情进展是由于白血病细胞中遗传不稳定性的发展。特别是，该疾病的两个阶段被认为反映了不同的、离散的遗传事件。此类事件目前仍不明确，而且所观察到的基因畸变的因果关系也不清楚。本文提出了另一种假说。假定反馈相互作用调节“定向”细胞以及多能细胞成熟和复制的相对概率，并且进一步假定所有阶段的有丝分裂细胞都具有相当大的表型适应性；特别是它们的自我更新能力会根据组织细胞组成的变化而改变，即使是在传统定义的区室范围内。在此基础上，研究表明慢性白血病可因单一克隆特征——成熟诱导性的逐渐下降而产生并演变为原始细胞危象。借助数学分析，研究展示了早期造血细胞中的初始可遗传事件如何导致组织紊乱，进而反馈到克隆的各个细胞成员，引发一系列动态变化，最终导致原始细胞占主导地位。
