Selvakumaran M, Reed J C, Liebermann D, Hoffman B
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140.
Blood. 1994 Aug 15;84(4):1036-42.
Hematopoiesis is a profound example of cell homeostasis that is regulated throughout life. This process requires the participation of many factors, including positive and negative regulators of growth and differentiation, that determine survival, growth stimulation, differentiation, functional activation, and programmed cell death. Understanding the effects of multiple stimuli on specific cells at the molecular and cellular level is crucial towards understanding how the population of blood cells maintains a homeostatic state. Two appropriate stimuli for analysis, both of which are found in bone marrow, are differentiation-inducing cytokines, which induce terminal differentiation associated with growth arrest, ultimately culminating in programmed cell death, and transforming growth factor-beta 1 (TGF-beta 1), which induces rapid growth arrest and apoptosis of hematopoietic cells. Previously, we have shown, using M1 myeloblastic leukemic cells as a model system, that differentiation-inducing cytokines induce terminal differentiation associated with growth arrest and, only after 5 to 7 days, apoptosis, whereas TGF-beta 1 induces rapid growth arrest and apoptosis. In this report, we show that M1 myeloid leukemic cells treated concomitantly with the differentiation inducer interleukin-6 and TGF-beta 1 undergo terminal differentiation, in which modulators of the MyD118 gene product, previously shown to be a positive regulator of TGF-beta 1-induced apoptosis, are implicated to play a role in protecting the cells from TGF-beta 1-induced apoptosis. Furthermore, using M1 cell variants blocked at different stages after induction of differentiation, including M1myb and M1myc, as well as conditionally blocked M1mycer, it has been shown that the dominance of interleukin-6 to TGF-beta 1-induced apoptosis is dependent on the progression of the differentiation program. Further studies with M1 and the genetically engineered M1 cell variants will be instrumental towards molecularly dissecting the interaction of hematopoietic differentiation with a variety of apoptotic pathways.
造血作用是细胞稳态的一个深刻例子，其在整个生命过程中都受到调控。这个过程需要许多因素的参与，包括生长和分化的正负调节因子，这些因子决定细胞的存活、生长刺激、分化、功能激活和程序性细胞死亡。在分子和细胞水平上理解多种刺激对特定细胞的影响，对于理解血细胞群体如何维持稳态至关重要。两种适合用于分析的刺激物都存在于骨髓中，一种是诱导分化的细胞因子，它诱导与生长停滞相关的终末分化，最终导致程序性细胞死亡；另一种是转化生长因子-β1（TGF-β1），它诱导造血细胞快速生长停滞和凋亡。此前，我们以M1髓母细胞白血病细胞作为模型系统，发现诱导分化的细胞因子诱导与生长停滞相关的终末分化，并且仅在5至7天后诱导凋亡，而TGF-β1则诱导快速生长停滞和凋亡。在本报告中，我们表明，同时用分化诱导剂白细胞介素-6和TGF-β1处理的M1髓系白血病细胞会发生终末分化，其中MyD118基因产物的调节因子（先前已证明是TGF-β1诱导凋亡的正调节因子）被认为在保护细胞免受TGF-β1诱导的凋亡中发挥作用。此外，使用在分化诱导后不同阶段被阻断的M1细胞变体，包括M1myb和M1myc，以及条件性阻断的M1mycer，已表明白细胞介素-6对TGF-β1诱导凋亡的主导作用取决于分化程序的进展。对M1和基因工程改造的M1细胞变体进行进一步研究，将有助于从分子层面剖析造血分化与多种凋亡途径之间的相互作用。
