The role of Ikaros in human erythroid differentiation
The role of Ikaros in human erythroid differentiation
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DOI：
10.1182/blood-2007-07-098202
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发表时间：
2008-02-01
期刊：
影响因子：
20.3
通讯作者：
Tonnelle, Cecile
中科院分区：
文献类型：
--
作者：
Dijon, Marilyne;Bardin, Florence;Tonnelle, Cecile
Ikaros-一种积极或消极控制基因转录的因子-在小鼠成体红细胞中是活跃的，并参与胎儿到成人珠蛋白的转换。具有Ikaros突变的小鼠具有红细胞生成缺陷和贫血。本文首次研究了Ikaros在人类红系发育中的作用。使用基因转移策略，我们表达了Ikaros 6（Ik 6）-一种已知的显性负性蛋白，干扰正常的Ikaros活性-在脐带血或单采CD 34（+）细胞，诱导分化沿着红细胞途径。慢病毒诱导的IK 6强制表达导致细胞死亡增加，细胞增殖减少，红系特异性基因，包括GATA 1和胎儿和成人球蛋白的表达减少。相反，我们观察到在该培养系统中可以检测到的残留髓样群体的维持，髓样基因表达相对增加，包括PU 1。在二次培养中，Ik 6的表达有利于分选的和表型确定的红系细胞逆转成髓系细胞，并防止髓系细胞逆转成红系细胞。我们的结论是，Ikaros参与人类成人或胎儿红系分化以及红系和髓系细胞之间的承诺。
Ikaros-a factor that positively or negatively controls gene transcription-is active in murine adult erythroid cells, and involved in fetal to adult globin switching. Mice with Ikaros mutations have defects in erythropoiesis and anemia. In this paper, we have studied the role of Ikaros in human erythroid development for the first time. Using a gene-transfer strategy, we expressed Ikaros 6 (Ik6)-a known dominant-negative protein that interferes with normal Ikaros activity-in cord blood or apheresis CD34(+) cells that were induced to differentiate along the erythroid pathway. Lentivirally induced Ik6-forced expression resulted in increased cell death, decreased cell proliferation, and decreased expression of erythroid-specific genes, including GATA1 and fetal and adult globins. In contrast, we observed the maintenance of a residual myeloid population that can be detected in this culture system, with a relative increase of myeloid gene expression, including PU1. In secondary cultures, expression of Ik6 favored reversion of sorted and phenotypically defined erythroid cells into myeloid cells, and prevented reversion of myeloid cells into erythroid cells. We conclude that Ikaros is involved in human adult or fetal erythroid differentiation as well as in the commitment between erythroid and myeloid cells.