Watson J D, Barber K E, Crosier P S
Department of Immunobiology, School of Medicine, University of Auckland, New Zealand.
Behring Inst Mitt. 1988 Aug(83):154-64.
Realising the therapeutic potential of colony-stimulating factors (CSFs) depends upon understanding the biological responses elicited by these regulators in target hemopoietic cells, and determining the biochemical nature of signals transduced through their receptors. These signals can lead to growth, differentiation or the activation of an effector function. CSF-dependent cells maintained in culture resemble pre-leukemic cells and releasing cells from a factor-dependent growth state must be a final step in leukemogenesis. The measurement of metabolic changes in cells following ligand-receptor interactions has thus far failed to reveal the biochemical identity of growth signal transducing events. The patterns of growth responses observed in various CSF-dependent cell lines provide some idea of the relationship of these events for different CSF species. A number of IL-3-dependent cell lines can be switched to an IL-2- or a GM-CSF-dependent growth state. This implies the intracellular pathways activated by signal transduction through their different receptors must be related. The expression of the v-src oncogene in IL-3- and GM-CSF-dependent cells leads to CSF-independent growth, whereas in an IL-2-dependent growth state the expression of v-src in these same cells does not lead to a loss of the requirement for IL-2 for growth. It might be argued that signal transduction through IL-3- or GM-CSF-specific receptors involves a protein tyrosine kinase. However, the addition of IL-3 or GM-CSF to cells expressing v-src results in a decrease in tyrosine kinase activity, suggesting that the effect of IL-3- or GM-CSF-specific signal transduction is to inhibit the expression of tyrosine kinase. It is unlikely that G-CSF signal transduction involves a receptor-associated tyrosine kinase. 32Dcl-23 cells respond to G-CSF by cell division and terminal differentiation, but when these cells are transformed to factor-independent growth following v-src infection, they remain responsive to G-CSF but lose the capacity to terminally differentiate. We have investigated the growth and differentiative responses of a range of human myeloid leukemias to G-CSF, IL-3 and GM-CSF. There is heterogeneity in the responses of different leukemic cells to these growth factors.(ABSTRACT TRUNCATED AT 400 WORDS)
认识到集落刺激因子（CSF）的治疗潜力，取决于了解这些调节因子在靶造血细胞中引发的生物学反应，并确定通过其受体转导的信号的生化性质。这些信号可导致生长、分化或效应功能的激活。培养中维持的CSF依赖细胞类似于白血病前期细胞，使细胞从因子依赖的生长状态中释放出来必定是白血病发生的最后一步。迄今为止，对配体-受体相互作用后细胞代谢变化的测量未能揭示生长信号转导事件的生化特性。在各种CSF依赖细胞系中观察到的生长反应模式，为这些事件与不同CSF种类之间的关系提供了一些线索。许多IL-3依赖细胞系可转换为IL-2或GM-CSF依赖的生长状态。这意味着通过其不同受体的信号转导激活的细胞内途径必定是相关的。在IL-3和GM-CSF依赖细胞中v-src癌基因的表达导致CSF非依赖生长，而在IL-2依赖的生长状态下，这些相同细胞中v-src的表达不会导致生长对IL-2需求的丧失。可能有人认为，通过IL-3或GM-CSF特异性受体的信号转导涉及一种蛋白酪氨酸激酶。然而，将IL-3或GM-CSF添加到表达v-src的细胞中会导致酪氨酸激酶活性降低，这表明IL-3或GM-CSF特异性信号转导的作用是抑制酪氨酸激酶的表达。G-CSF信号转导不太可能涉及与受体相关的酪氨酸激酶。32Dcl-23细胞通过细胞分裂和终末分化对G-CSF作出反应，但当这些细胞在v-src感染后转化为因子非依赖生长时，它们仍对G-CSF有反应，但失去了终末分化的能力。我们研究了一系列人类髓系白血病对G-CSF、IL-3和GM-CSF的生长和分化反应。不同白血病细胞对这些生长因子的反应存在异质性。（摘要截短于400字）
