Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay.
Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay.
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DOI：
10.3324/haematol.2019.244541
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发表时间：
2021-04-01
期刊：
影响因子：
10.1
通讯作者：
Vyas P
中科院分区：
文献类型：
--
作者：
Juban G;Sakakini N;Chagraoui H;Cruz Hernandez D;Cheng Q;Soady K;Stoilova B;Garnett C;Waithe D;Otto G;Doondeea J;Usukhbayar B;Karkoulia E;Alexiou M;Strouboulis J;Morrissey E;Roberts I;Porcher C;Vyas P
当造血转录因子 GATA1 的 N 末端截短突变（产生 GATA1 短蛋白 (GATA1s)）在发育早期获得时，唐氏综合症 (DS) 新生儿中的巨核细胞/红系短暂性骨髓增殖性疾病 (TMD) 就会发生。先前的研究表明，小鼠 GATA1 本身会引起暂时性卵黄囊骨髓增殖性疾病。然而，尚不清楚 GATA1 在造血细胞层次结构中的哪个位置发挥其作用以产生这种骨髓增殖状态。在这里，通过对小鼠 GATA1s 胚胎干细胞 (ESC) 和 GATA1s 胚胎的造血作用的详细检查，我们定义了造血后期发生的红细胞和巨核细胞分化缺陷。 GATA1s 会导致体内红系分化晚期停滞，在 ESC 衍生的培养物中影响更严重，Ter-119 细胞显着减少，红系基因表达减少。在巨核细胞生成过程中，GATA1 会导致特定阶段的分化延迟，并导致表达 CD41hi 的未成熟巨核细胞的积累。在这个特定的巨核细胞区室中，与同一细胞区室中的 GATA1 细胞相比，处于细胞周期 S 期的 GATA1s 细胞数量增加，而凋亡细胞数量减少。与同一分化阶段的 GATA1 细胞相比，这些未成熟的 GATA1s 巨核细胞谱系细胞的成熟也存在延迟。最后，即使 GATA1 巨核细胞成熟，它们也会异常成熟，并改变巨核细胞特异性基因表达和成熟巨核细胞酶乙酰胆碱酯酶的活性。这些研究精确定位了 GATA1 巨核细胞骨髓增殖发生的造血区室，确定了分子研究现在应重点关注的部位，以了解 GATA1 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.
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影响因子：
9.8
作者：
Kadri Z;Shimizu R;Ohneda O;Maouche-Chretien L;Gisselbrecht S;Yamamoto M;Romeo PH;Leboulch P;Chretien S
通讯作者：
Chretien S
影响因子：
8.8
作者：
McGrath KE;Frame JM;Fegan KH;Bowen JR;Conway SJ;Catherman SC;Kingsley PD;Koniski AD;Palis J
通讯作者：
Palis J
影响因子：
5.3
作者：
KELLER, G;KENNEDY, M;WILES, MV
通讯作者：
WILES, MV
影响因子：
20.3
作者：
Dubart, A;Romeo, PH;Dumenil, D
通讯作者：
Dumenil, D
影响因子：
20.3
作者：
Gregory, T;Yu, CN;Weiss, MJ
通讯作者：
Weiss, MJ