Eaves A C, Cashman J D, Gaboury L A, Kalousek D K, Eaves C J
Proc Natl Acad Sci U S A. 1986 Jul;83(14):5306-10. doi: 10.1073/pnas.83.14.5306.
Previous studies have shown that Philadelphia (Ph1) chromosome-positive chronic myeloid leukemia (CML) results from the abnormal expansion at the pluripotent stem cell level of a single clone of hemopoietic cells. Although it seems likely that this is related to the heightened proliferative activity characteristic of primitive CML progenitor cell types, the underlying mechanism is unknown. In this report we show that either normal or CML peripheral blood progenitors can be maintained on preestablished normal marrow adherent layers for periods of 1-2 months. Under these conditions numbers of both normal and neoplastic progenitors are usually higher in the adherent layer than in the nonadherent fraction. Moreover, the number of primitive progenitors of high proliferative potential present in the adherent layer is sufficient to allow their cycling status to be determined. Such measurements demonstrate that primitive normal progenitors of blood origin, when cultured in the presence of a preestablished adherent marrow feeder layer, go in and out of cycle after each medium change but in the absence of a feeder layer remain continuously in cycle. In contrast, primitive CML progenitors of either blood or marrow origin cycle continuously regardless of the presence or absence of an adherent feeder layer. We suggest that early expansion of the CML clone is related to an ability of the neoplastic stem cells to ignore or overcome a negative regulatory signal produced by nonneoplastic adherent marrow cells whose normal function is to maintain the stem cell reserve in a quiescent state.
先前的研究表明，费城（Ph1）染色体阳性的慢性髓性白血病（CML）是由造血细胞单个克隆在多能干细胞水平的异常扩增所致。尽管这似乎可能与原始CML祖细胞类型所特有的增殖活性增强有关，但其潜在机制尚不清楚。在本报告中，我们表明正常或CML外周血祖细胞均可在预先建立的正常骨髓贴壁层上维持1 - 2个月。在这些条件下，贴壁层中正常和肿瘤祖细胞的数量通常高于非贴壁部分。此外，贴壁层中存在的具有高增殖潜力的原始祖细胞数量足以确定其循环状态。这些测量结果表明，血液来源的原始正常祖细胞在预先建立的贴壁骨髓饲养层存在的情况下，每次更换培养基后会进入和退出细胞周期，但在没有饲养层的情况下会持续处于细胞周期中。相比之下，血液或骨髓来源的原始CML祖细胞无论是否存在贴壁饲养层都会持续循环。我们认为，CML克隆的早期扩增与肿瘤干细胞忽略或克服由非肿瘤性贴壁骨髓细胞产生的负调节信号的能力有关，这些非肿瘤性贴壁骨髓细胞的正常功能是使干细胞储备维持在静止状态。
