Pluripotent stem cell model of early hematopoiesis in Down syndrome reveals quantitative effects of short-form GATA1 protein on lineage specification.
Pluripotent stem cell model of early hematopoiesis in Down syndrome reveals quantitative effects of short-form GATA1 protein on lineage specification.
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DOI：
10.1371/journal.pone.0247595
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Saito MK
中科院分区：
文献类型：
--
作者：
Matsuo S;Nishinaka-Arai Y;Kazuki Y;Oshimura M;Nakahata T;Niwa A;Saito MK
唐氏综合征（DS）儿童易患两种血液疾病，即短暂性异常骨髓生成（TAM）和唐氏综合征相关急性巨核细胞白血病（DS-AMKL）。加塔结合蛋白1（GATA 1）的突变已被鉴定为这些疾病的原因，并且已知所得蛋白质短形式GATA 1（GATA 1 s）的表达水平与TAM的严重程度相关。另一方面，尽管在几乎所有DS-AMKL病例中存在GATA 1突变，但TAM患者中DS-AMKL的发生率与GATA 1表达呈负相关。这一发现需要澄清GATA 1在产生与这两种疾病风险相关的起源细胞中的作用。着眼于这一点，我们研究了GATA 1突变体三体性-21多能干细胞的特点转染与多西环素（Dox）诱导GATA 1 s表达盒中的逐步造血分化方案。我们发现，更高的GATA 1 s表达显着减少承诺成巨核细胞谱系在早期造血祖细胞（HPC）阶段，但一旦承诺，效果是逆转的祖细胞，并采取行动，以维持祖细胞。这些分化阶段依赖性逆转效应与髓系的结果相反，在髓系中，GATA 1只是维持和增加未成熟髓系细胞的数量。这些结果表明，尽管GATA 1突变细胞引起髓系和巨核系祖细胞的增加，而不管GATA 1 s表达的强度如何，但途径随表达水平而变化。这项研究为GATA 1突变在这两种疾病中的矛盾临床特征提供了实验支持。
Children with Down syndrome (DS) are susceptible to two blood disorders, transient abnormal myelopoiesis (TAM) and Down syndrome-associated acute megakaryocytic leukemia (DS-AMKL). Mutations in GATA binding protein 1 (GATA1) have been identified as the cause of these diseases, and the expression levels of the resulting protein, short-form GATA1 (GATA1s), are known to correlate with the severity of TAM. On the other hand, despite the presence of GATA1 mutations in almost all cases of DS-AMKL, the incidence of DS-AMKL in TAM patients is inversely correlated with the expression of GATA1s. This discovery has required the need to clarify the role of GATA1s in generating the cells of origin linked to the risk of both diseases. Focusing on this point, we examined the characteristics of GATA1 mutant trisomy-21 pluripotent stem cells transfected with a doxycycline (Dox)-inducible GATA1s expression cassette in a stepwise hematopoietic differentiation protocol. We found that higher GATA1s expression significantly reduced commitment into the megakaryocytic lineage at the early hematopoietic progenitor cell (HPC) stage, but once committed, the effect was reversed in progenitor cells and acted to maintain the progenitors. These differentiation stage-dependent reversal effects were in contrast to the results of myeloid lineage, where GATA1s simply sustained and increased the number of immature myeloid cells. These results suggest that although GATA1 mutant cells cause the increase in myeloid and megakaryocytic progenitors regardless of the intensity of GATA1s expression, the pathways vary with the expression level. This study provides experimental support for the paradoxical clinical features of GATA1 mutations in the two diseases.
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影响因子：
17.1
作者：
Doulatov S;Vo LT;Macari ER;Wahlster L;Kinney MA;Taylor AM;Barragan J;Gupta M;McGrath K;Lee HY;Humphries JM;DeVine A;Narla A;Alter BP;Beggs AH;Agarwal S;Ebert BL;Gazda HT;Lodish HF;Sieff CA;Schlaeger TM;Zon LI;Daley GQ
通讯作者：
Daley GQ
影响因子：
20.3
作者：
Gamis, Alan S.;Alonzo, Todd A.;Smith, Franklin O.
通讯作者：
Smith, Franklin O.
影响因子：
20.3
作者：
Hitzler, JK;Cheung, J;Zipursky, A
通讯作者：
Zipursky, A
影响因子：
20.3
作者：
Roberts, Irene;Alford, Kate;Vyas, Paresh
通讯作者：
Vyas, Paresh
影响因子：
11.4
作者：
Maroz, A.;Stachorski, L.;Klusmann, J-H
通讯作者：
Klusmann, J-H