Granulocyte colony-stimulating factor (GCSF) administration has been linked to the development of monosomy 7 in severe congenital neutropenia and aplastic anemia. We assessed the effect of pharmacologic doses of GCSF on monosomy 7 cells to determine whether this chromosomal abnormality developed de novo or arose as a result of favored expansion of a preexisting clone. Fluorescence in situ hybridization (FISH) of chromosome 7 was used to identify small populations of aneuploid cells. When bone marrow mononuclear cells from patients with monosomy 7 were cultured with 400 ng/ml GCSF, all samples showed significant increases in the proportion of monosomy 7 cells. In contrast, bone marrow from karyotypically normal aplastic anemia, myelodysplastic syndrome, or healthy individuals did not show an increase in monosomy 7 cells in culture. In bone marrow CD34 cells of patients with myelodysplastic syndrome and monosomy 7, GCSF receptor (GCSFR) protein was increased. Although no mutation was found in genomic GCSFR DNA, CD34 cells showed increased expression of the GCSFR class IV mRNA isoform, which is defective in signaling cellular differentiation. GCSFR signal transduction via the Jak/Stat system was abnormal in monosomy 7 CD34 cells, with increased phosphorylated signal transducer and activation of transcription protein, STAT1-P, and increased STAT5-P relative to STAT3-P. Our results suggest that pharmacologic doses of GCSF increase the proportion of preexisting monosomy 7 cells. The abnormal response of monosomy 7 cells to GCSF would be explained by the expansion of undifferentiated monosomy 7 clones expressing the class IV GCSFR, which is defective in signaling cell maturation.

译文

:粒细胞集落刺激因子(GCSF)的管理与严重先天性中性粒细胞减少和再生障碍性贫血的7号单体病的发展有关。我们评估了药理学剂量的GCSF对7号单体细胞的影响,以确定这种染色体异常是从头发展还是由于已有克隆的有利扩增而出现。 7号染色体的荧光原位杂交(FISH)用于鉴定少量非整倍体细胞。当用400 ng / ml GCSF培养来自第7号单体患者的骨髓单个核细胞时,所有样品均显示出第7号单体细胞的比例显着增加。相反,来自核型正常再生障碍性贫血,骨髓增生异常综合症或健康个体的骨髓在培养物中未显示单核7细胞的增加。在骨髓增生异常综合症和7号单体症患者的骨髓CD34细胞中,GCSF受体(GCSFR)蛋白增加。尽管在基因组GCSFR DNA中未发现突变,但CD34细胞显示GCSFR IV类mRNA亚型的表达增加,这在信号细胞分化中是有缺陷的。通过Jak / Stat系统进行的GCSFR信号转导在7号单体CD34细胞中异常,磷酸化信号转导子的增加和转录蛋白STAT1-P的激活以及相对于STAT3-P的STAT5-P的增加。我们的结果表明,GCSF的药理剂量增加了先前存在的单核7细胞的比例。 7号单体细胞对GCSF的异常应答可以通过表达IV类GCSFR的未分化的7号单体克隆的扩增来解释,该克隆在信号细胞的成熟中是有缺陷的。

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