Miyauchi J, Kelleher C A, Wong G G, Yang Y C, Clark S C, Minkin S, Minden M D, McCulloch E A
The Ontario Cancer Institute, Toronto, Canada.
Leukemia. 1988 Jun;2(6):382-7.
The blast cells of acute myeloblastic leukemia may be considered as a renewal population maintained by stem cells that are capable of both self-renewal and differentiation. Blast stem cells grow in culture usually when stimulated by growth factors normally active on myelopoietic cells. Two culture methods permit an evaluation of the balance between self-renewal and differentiation; previous studies have shown that this balance can be affected by recombinant growth factors. These include interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF), active on early cells in normal myelopoiesis, and G-CSF and CSF-1, restricted in normal hemopoiesis to the granulopoietic and macrophage/monocytic lineages, respectively. In this paper we report the results of evaluating the effects on these recombinant growth factors alone or in mixtures of two at optimal concentrations. The results were obtained either using titrations of colony formation in methylcellulose or growth in suspension. Star diagrams, a technique from exploratory data analysis, were used to provide quantitative and graphic displays of the results of the recombinant factors on the balance between blast self-renewal and differentiation. Blasts from 4 acute myeloblastic leukemia patients and one patient with the blast crisis of chronic myeloblastic leukemia were examined in detail. The great patient-to-patient variation usually observed was seen in both plating efficiency in methylcellulose and growth pattern in suspension. In spite of this variation, a common pattern of response to growth factors emerged. When the early acting factors, IL-3 and GM-CSF, were combined, the effect was quantitatively and qualitatively similar to the largest stimulation seen with either of the factors alone. In contrast, late-acting factors, G-CSF and CSF-1, influenced each other's effects when present together and each affected the activities of GM-CSF and IL-3. Notably, CSF-1, which often led to the accumulation of adherent, terminal cells in suspension, usually maintained or increased this differentiation-like activity in combination. G-CSF also favored differentiation in combination, although the effect was usually to increase the number of colonies in methylcellulose, most of which consist of blast cells incapable of further divisions. The results are discussed as they relate to the postulated structure of the blast population and the normal targets of the recombinant growth factors.
急性髓细胞白血病的原始细胞可被视为由具有自我更新和分化能力的干细胞维持的更新群体。原始干细胞通常在正常作用于骨髓细胞的生长因子刺激下在培养中生长。两种培养方法可用于评估自我更新和分化之间的平衡；先前的研究表明，这种平衡会受到重组生长因子的影响。这些因子包括白细胞介素3（IL-3）和粒细胞-巨噬细胞集落刺激因子（GM-CSF），它们在正常骨髓生成中作用于早期细胞，以及G-CSF和CSF-1，在正常造血过程中分别限于粒细胞生成和巨噬细胞/单核细胞谱系。在本文中，我们报告了评估这些重组生长因子单独或两种因子以最佳浓度混合使用时的效果的结果。结果是通过在甲基纤维素中滴定集落形成或在悬浮液中生长获得的。星图是探索性数据分析中的一种技术，用于提供重组因子对原始细胞自我更新和分化之间平衡影响的定量和图形展示。对4例急性髓细胞白血病患者和1例慢性髓细胞白血病急变期患者的原始细胞进行了详细检查。通常观察到的患者间巨大差异在甲基纤维素中的接种效率和悬浮液中的生长模式中均可见到。尽管存在这种差异，但对生长因子的共同反应模式还是出现了。当早期作用因子IL-3和GM-CSF联合使用时，其效果在数量和质量上与单独使用任何一种因子时观察到的最大刺激相似。相比之下，晚期作用因子G-CSF和CSF-1一起存在时会相互影响彼此的效果，并且各自都会影响GM-CSF和IL-3的活性。值得注意的是，CSF-1通常会导致悬浮液中贴壁的终末细胞积累，通常在联合使用时会维持或增加这种类似分化的活性。G-CSF联合使用时也有利于分化，尽管其效果通常是增加甲基纤维素中集落的数量，其中大多数集落由无法进一步分裂的原始细胞组成。讨论了这些结果与原始细胞群体的假定结构以及重组生长因子的正常靶点之间的关系。
