Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay
Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay
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致癌Gata1导致阶段特异性巨核细胞分化延迟
DOI：
10.1101/791079
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Juban G
中科院分区：
文献类型：
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作者：
Juban G
唐氏综合征（Down syndrome，DS）新生儿的巨核细胞/红细胞暂时性骨髓增生性疾病（megakaryocyte/erythroid transient myeloproliferative disorder，TMD）发生于造血转录因子GATA 1的N端截短突变，产生GATA 1短蛋白（GATA 1 s），在发育早期获得。先前的研究表明，鼠GATA 1本身会引起暂时性卵黄囊骨髓增生性疾病。然而，目前尚不清楚GATA 1在造血细胞层次中的何处发挥其作用以产生这种骨髓增殖状态。在这里，通过对小鼠GATA 1 s胚胎干细胞（ESC）和GATA 1 s胚胎造血的详细检查，我们定义了造血后期发生的红细胞和巨核细胞分化缺陷。GATA 1 s在体内引起红系分化晚期的停滞，在ESC衍生的培养物中甚至更深刻地引起停滞，Ter-119细胞显著减少，红系基因表达减少。在巨核细胞生成中，GATA 1在特定阶段导致分化延迟，并积累未成熟的表达kit的CD 41 hi巨核细胞。在这种特定的巨核细胞区室中，与相同细胞区室中的GATA 1细胞相比，细胞周期S期的GATA 1 s细胞数量增加，凋亡细胞数量减少。与处于同一分化阶段的GATA 1细胞相比，这些未成熟的GATA 1 s巨核细胞谱系细胞的成熟也有延迟。最后，即使当GATA 1 s巨核细胞成熟，他们成熟异常改变巨核细胞特异性基因表达和活性的成熟巨核细胞酶，乙酰胆碱酯酶。这些研究查明了GATA 1巨核细胞骨髓增生发生的造血区室，定义了分子研究现在应该集中在哪里以了解GATA 1的致癌作用。
The megakaryocyte/erythroid transient myeloproliferative disorder (TMD) in newborns with Down syndrome (DS) occurs when Nterminal truncating mutations of the hemopoietic transcription factor GATA1, that produce GATA1short protein (GATA1s), are acquired early in development. Prior work has shown that murine GATA1s, by itself, causes a transient yolk sac myeloproliferative disorder. However, it is unclear where in the hemopoietic cellular hierarchy GATA1s exerts its effects to produce this myeloproliferative state. Here, through a detailed examination of hemopoiesis from murine GATA1s embryonic stem cells (ESC) and GATA1s embryos we define defects in erythroid and megakaryocytic differentiation that occur late in hemopoiesis. GATA1s causes an arrest late in erythroid differentiation in vivo, and even more profoundly in ESC-derived cultures, with a marked reduction of Ter-119 cells and reduced erythroid gene expression. In megakaryopoiesis, GATA1s causes a differentiation delay at a specific stage, with accumulation of immature, kit-expressing CD41hi megakaryocytic cells. In this specific megakaryocytic compartment, there are increased numbers of GATA1s cells in S-phase of the cell cycle and a reduced number of apoptotic cells compared to GATA1 cells in the same cell compartment. There is also a delay in maturation of these immature GATA1s megakaryocytic lineage cells compared to GATA1 cells at the same stage of differentiation. Finally, even when GATA1s megakaryocytic cells mature, they mature aberrantly with altered megakaryocyte-specific gene expression and activity of the mature megakaryocyte enzyme, acetylcholinesterase. These studies pinpoint the hemopoietic compartment where GATA1s megakaryocyte myeloproliferation occurs, defining where molecular studies should now be focused to understand the oncogenic action of GATA1s.