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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Regulated expression of P210 Bcr-Abl during embryonic stem cell differentiation stimulates multipotential progenitor expansion and myeloid cell fate
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Regulated expression of P210 Bcr-Abl during embryonic stem cell differentiation stimulates multipotential progenitor expansion and myeloid cell fate

机译：胚胎干细胞分化过程中P210 Bcr-Abl的调控表达刺激多能祖细胞扩增和骨髓细胞命运

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摘要

P210 Bcr-AbI is an activated tyrosine kinase oncogene encoded by the Philadelphia chromosome associated with human chronic my- elogenous leukemia (CM L). The disease represents a clonal disorder arising in the pluripotent hematopoietic stem cell. During the chronic phase. patients present with a dramatic expansion of myeloid cells and a mild anemia. Retroviral gene transfer and transgenic expression in rodents have demonstrated the ability of Bcr-Abl to induce various types of leukemia. However, study of human CML or rodent models has not determined the direct and immediate effects of Bcr-AbI on hematopoietic cells from those requiring secondary genetic or epigenetic changes selected during the pathogenic process. We utiIized tetracycIine-regulated expres- sion of Bcr-Abl from a promoter engineered for robust expression in primitive stem ceIls through multilineage bIood cell develop- ment in combination with the in vitto differentiation of embryonal stem cells into hematopoietic elements. Our results demonstrate that Bcr-AbI expression alone is sufficient to increase the number of multipotent and myeloid lineage committed progenitors in a dose-dependent manner while suppressing the development of committed erythroid progenitors. These effects are reversible upon extinguishing Bcr-Abl expression. These findings are consistent with Bcr-AbI being the sole genetic change needed for the estab- lishment of the chronic phase of CML and provide a powerful system for the analysis of any genetic change that alters cell growth and lineage choices of the hematopoietic stem cell.
机译：P210 Bcr-AbI是一种活化的酪氨酸激酶癌基因，由与人类慢性粒细胞性白血病（CM L）相关的费城染色体编码。该疾病代表多能造血干细胞中产生的克隆性疾病。在慢性期。患者表现出髓样细胞急剧扩增和轻度贫血。啮齿动物中的逆转录病毒基因转移和转基因表达证明了Bcr-Abl诱导各种类型白血病的能力。然而，对人类CML或啮齿动物模型的研究尚未确定Bcr-AbI对造血细胞的直接和直接作用，而这些作用需要那些在病原过程中需要进行二次遗传或表观遗传学改变的细胞。我们通过启动子对四环素调节的Bcr-Abl的表达进行了设计，该启动子经过工程设计，可通过多谱系血液细胞发育与胚胎干细胞在体内分化为造血成分，在原始干细胞中稳定表达。我们的结果表明，单独的Bcr-AbI表达足以以剂量依赖的方式增加多能谱系和髓系谱系定型祖细胞的数量，同时抑制定型红系祖细胞的发育。消除Bcr-Abl表达后，这些作用是可逆的。这些发现与Bcr-AbI是建立CML慢性期所需的唯一遗传改变相吻合，并为分析改变细胞生长和造血干细胞谱系选择的任何遗传改变提供了强大的系统。

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