FU Hematology and Department of Laboratory Medicine, Azienda Ospedaliero Universitaria (AOU) Careggi, University of Florence, Florence, Italy.
Clin Cancer Res. 2012 Jun 1;18(11):3079-89. doi: 10.1158/1078-0432.CCR-11-0686. Epub 2012 Apr 11.
Myelodysplastic syndromes (MDS) are heterogeneous clonal diseases characterized by cytopenias as a result of ineffective hematopoiesis. Little is known about alterations in signal transduction pathways in MDS.
Multiparameter flow cytometry was used to evaluate the proteolytic activation of caspase-3 and the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), and STAT5 specifically in defined CD34(+), CD45(+), or CD71(+)CD45(-) bone marrow (BM) cells from 60 MDS cases and normal controls, both at baseline and following stimulation with granulocyte colony-stimulating factor (G-CSF) and erythropoietin.
In CD71(+)CD45(-) cells from a subpopulation of 36 MDS cases who were predicted to be responsive by clinical parameters (endogenous erythropoietin levels, transfusion dependency, percentage of blasts in the BM), erythropoietin failed to activate ERK1/2 or STAT5 in 23 of 36 cases, but it was effective in 13 of 36 cases, although to a significantly lower degree than in CD71(+)CD45(-) cells from healthy donor BM. The erythropoietin response in vivo correlated with in vitro erythropoietin-dependent STAT5 activation in 20 of 22 cases. STAT5 was significantly activated at baseline in MDS cells compared with normal controls, whereas caspase-3 was activated in CD34(+) and CD45(+) MDS cells, and was activated more often in the RA and RAEB-1 MDS subtypes. G-CSF stimulation activated ERK1/2 and STAT5 equally in MDS and normal CD34(+) cells.
Abnormalities in the response to growth factors are restricted to erythropoietin stimulation in CD71(+)CD45(-) cells and correlate with the clinical response to erythropoietin. Activation of baseline signal transduction for proliferative and apoptotic signals is altered in MDS but with different patterns among the various BM subpopulations.
骨髓增生异常综合征（MDS）是一种异质性克隆疾病，其特征为无效造血导致的血细胞减少。目前对于 MDS 中信号转导途径的改变知之甚少。
使用多参数流式细胞术评估 caspase-3 的蛋白水解激活以及细胞外信号调节激酶（ERK）1/2、p38 有丝分裂原激活蛋白激酶（MAPK）和 STAT5 的磷酸化，这些蛋白的磷酸化在 60 例 MDS 病例和正常对照者的基线以及粒系集落刺激因子（G-CSF）和促红细胞生成素刺激后的特定 CD34+、CD45+或 CD71+CD45-骨髓（BM）细胞中被评估。
在通过临床参数（内源性促红细胞生成素水平、输血依赖性、BM 中原始细胞的百分比）预测为有反应的 36 例 MDS 病例的亚群的 CD71+CD45-细胞中，促红细胞生成素未能激活 ERK1/2 或 STAT5，但在 36 例中的 23 例中有效，尽管其效果明显低于正常供体 BM 中的 CD71+CD45-细胞。22 例中有 20 例体内促红细胞生成素反应与体外促红细胞生成素依赖性 STAT5 激活相关。与正常对照组相比，MDS 细胞的 STAT5 在基线时明显被激活，而 caspase-3 在 CD34+和 CD45+MDS 细胞中被激活，并且在 RA 和 RAEB-1 MDS 亚型中更常被激活。G-CSF 刺激在 MDS 和正常 CD34+细胞中同等激活 ERK1/2 和 STAT5。
生长因子反应异常仅限于 CD71+CD45-细胞中的促红细胞生成素刺激，并与促红细胞生成素的临床反应相关。在 MDS 中，增殖和凋亡信号的基线信号转导激活被改变，但在不同的 BM 亚群中具有不同的模式。
