Zhang D E, Hohaus S, Voso M T, Chen H M, Smith L T, Hetherington C J, Tenen D G
Hematology/Oncology Division, Beth Israel Hospital, Harvard Medical School, Boston, MA 02215, USA.
Curr Top Microbiol Immunol. 1996;211:137-47. doi: 10.1007/978-3-642-85232-9_14.
Our studies of the promoters of the myeloid CSF receptors (M, GM, and G) in cell lines have led to the findings that the promoters are small, and are all activated by the PU.1 and C/EBP proteins. To date, we have only found evidence for involvement of C/EBP alpha, although further experiments will be needed to exclude the role of C/EBP beta and C/EBP delta in receptor gene expression. These studies suggest a model of hematopoiesis (Fig. 2) in which the lineage commitment decisions of multipotential cells are made by the alternative patterns of expression of certain transcription factors, which then activate growth factor receptors which allow those cells to respond to the appropriate growth factor to proliferate and survive. For example, expression of GATA-1 activates its own expression, as well as that of the erythropoietin receptor, inducing these cells to be capable of responding to erythropoietin. Similarly, expression of PU.1 activates its own promoter, and turns on the three myeloid CSF receptors (M, GM, and G), pushing these cells along the pathway of myeloid differentiation. C/EBP proteins, particularly C/EBP alpha, are also critical for myeloid receptor promoter function, and may also act via autoregulatory mechanisms. Murine C/EBP alpha has a C/EBP binding site in its own promoter. Human C/EBP alpha autoregulates its own expression in adipocytes by activating the USF transcription factor. Myeloid genes expressed later during differentiation, such as CD11b, are also activated by PU.1, which is expressed at highest levels in mature myeloid cells, but not by C/EBP alpha, which is downregulated in a differentiated murine myeloid cell line. Consistent with this model are the findings that overexpression of PU.1 in erythroid cells blocks erythroid differentiation, leading to erythroleukemia, and overexpression of GATA-1 in a myeloid line blocks myeloid differentiation. While these findings have provided some framework for understanding myeloid gene regulation, there are a number of critical questions to be addressed in the near future: What is the pattern of expression of the C/EBP proteins during the course of myeloid differentiation and activation of human CD34+ cells? What is the effect of targeted disruption and other mutations of the C/EBP and AML1 proteins on myeloid development and receptor expression? What are the interactions among these three different types of factors (ets, basic region-zipper, and Runt domain proteins) to activate the promoters? What is the effect of translocations, mutations, and alterations in expression of these factors, particularly in different forms of AML?
我们对细胞系中髓系集落刺激因子受体（M、GM和G）启动子的研究发现，这些启动子很小，且均由PU.1和C/EBP蛋白激活。迄今为止，我们仅发现C/EBPα参与其中的证据，不过还需要进一步实验来排除C/EBPβ和C/EBPδ在受体基因表达中的作用。这些研究提示了一种造血模型（图2），其中多能细胞的谱系定向决定是由某些转录因子的交替表达模式做出的，这些转录因子随后激活生长因子受体，使这些细胞能够对相应的生长因子做出反应以增殖和存活。例如，GATA-1的表达激活其自身表达以及促红细胞生成素受体的表达，诱导这些细胞能够对促红细胞生成素做出反应。同样，PU.1的表达激活其自身启动子，并开启三种髓系集落刺激因子受体（M、GM和G），推动这些细胞沿着髓系分化途径发展。C/EBP蛋白，尤其是C/EBPα，对髓系受体启动子功能也至关重要，并且可能也通过自调节机制发挥作用。小鼠C/EBPα在其自身启动子中有一个C/EBP结合位点。人C/EBPα通过激活USF转录因子在脂肪细胞中自调节其自身表达。在分化后期表达的髓系基因，如CD11b，也由PU.1激活，PU.1在成熟髓系细胞中表达水平最高，但不由C/EBPα激活，C/EBPα在分化的小鼠髓系细胞系中表达下调。与该模型一致的是，在红系细胞中过表达PU.1会阻断红系分化，导致红白血病，而在髓系细胞系中过表达GATA-1会阻断髓系分化。虽然这些发现为理解髓系基因调控提供了一些框架，但在不久的将来仍有许多关键问题需要解决：在人CD34+细胞的髓系分化和激活过程中，C/EBP蛋白的表达模式是怎样的？C/EBP和AML1蛋白的靶向破坏及其他突变对髓系发育和受体表达有何影响？这三种不同类型的因子（ets、碱性区域-拉链和Runt结构域蛋白）之间相互作用以激活启动子的情况是怎样的？这些因子的易位、突变和表达改变，尤其是在不同形式的急性髓系白血病（AML）中的影响是什么？
