Eaves C J, Cashman J D, Wolpe S D, Eaves A C
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):12015-9. doi: 10.1073/pnas.90.24.12015.
Most primitive hematopoietic cells appear to be normally quiescent in vivo, whereas their leukemic counterparts in patients with chronic myeloid leukemia (CML) are maintained in a state of rapid turnover. This difference is also seen in the long-term culture system, where control of primitive hematopoietic progenitor proliferation is mediated by interactions of these cells with marrow-derived mesenchymal cells of the fibroblast lineage. We now show that exogenous addition of macrophage inflammatory protein 1 alpha (MIP-1 alpha) to normal long-term cultures can reversibly and specifically block the activation of "primitive" (high proliferative potential), but not "mature" (lower proliferative potential), progenitors in the adherent layer of these cultures. Moreover, addition of MIP-1 beta after primitive-progenitor activation can prevent the subsequent return of these cells to a quiescent state a few days later as shown previously in similar experiments using antibodies to transforming growth factor beta. This suggests that the level of MIP-1 alpha (or a related MIP-1 alpha agonist) produced in LTCs, like the level of transforming growth factor beta, may be necessary, but is not on its own sufficient, to mediate the inhibitory activity of the regulatory cells in the adherent layer. Addition of MIP-1 alpha to similar long-term cultures containing normal marrow adherent layers but supporting exclusively neoplastic (CML) hematopoiesis did not block the cycling of primitive neoplastic progenitors. A defect in the responsiveness of CML cells to MIP-1 alpha (or a similarly acting chemokine) would explain their deregulated proliferative behavior in this model and, by extrapolation to the in vivo setting, suggests a molecular mechanism whereby the leukemic clone may become amplified at the stem-cell level. In addition, these findings suggest approaches to the therapy of CML, using inhibitors such as MIP-1 alpha for the protection of primitive normal cells.
大多数原始造血细胞在体内似乎处于正常的静止状态，而慢性髓性白血病（CML）患者体内的白血病对应细胞则维持在快速更新的状态。在长期培养系统中也观察到了这种差异，其中原始造血祖细胞增殖的控制是由这些细胞与成纤维细胞系的骨髓间充质细胞相互作用介导的。我们现在表明，向正常长期培养物中外源添加巨噬细胞炎性蛋白1α（MIP-1α）可以可逆且特异性地阻断这些培养物贴壁层中“原始”（高增殖潜能）而非“成熟”（低增殖潜能）祖细胞的激活。此外，如先前在使用转化生长因子β抗体的类似实验中所示，在原始祖细胞激活后添加MIP-1β可以防止这些细胞在几天后恢复到静止状态。这表明，长期培养物中产生的MIP-1α（或相关的MIP-1α激动剂）水平，与转化生长因子β水平一样，可能是介导贴壁层中调节细胞抑制活性所必需的，但仅靠其自身并不足够。向含有正常骨髓贴壁层但仅支持肿瘤性（CML）造血的类似长期培养物中添加MIP-1α，并未阻断原始肿瘤祖细胞的循环。CML细胞对MIP-1α（或类似作用的趋化因子）反应性的缺陷可以解释它们在该模型中失控的增殖行为，并且由此推断到体内情况，提示了一种分子机制，通过该机制白血病克隆可能在干细胞水平上扩增。此外，这些发现提示了CML的治疗方法，即使用MIP-1α等抑制剂来保护原始正常细胞。
