PHF6 Expression Levels Impact Human Hematopoietic Stem Cell Differentiation.
PHF6 Expression Levels Impact Human Hematopoietic Stem Cell Differentiation.
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DOI：
10.3389/fcell.2020.599472
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发表时间：
2020
影响因子：
5.5
通讯作者：
Taghon T
中科院分区：
文献类型：
--
作者：
Loontiens S;Dolens AC;Strubbe S;Van de Walle I;Moore FE;Depestel L;Vanhauwaert S;Matthijssens F;Langenau DM;Speleman F;Van Vlierberghe P;Durinck K;Taghon T
造血的转录控制涉及复杂的调控网络，这些组成部分之一的功能扰动往往导致恶性肿瘤。PHF 6的功能丧失突变，编码一种假定的表观遗传调节因子，主要在T细胞急性淋巴细胞白血病（T-ALL）中描述，最近才从小鼠模型实验中首次了解其在正常造血中的功能。在这里，我们通过在脐带血和胸腺来源的造血前体中进行敲低研究来研究PHF 6在人血细胞发育中的作用，以评估在良好建立的体外模型中对谱系分化的影响。我们的研究结果表明，PHF 6水平差异影响人类造血祖细胞分化成各种血细胞谱系，淋巴和红细胞分化的显着影响。我们发现PHF 6的缺失通过减少NOTCH 1及其下游靶基因的表达而导致人类T细胞发育加速。这种功能性的相互作用在胸腺细胞的发展中得到证实，在体内使用phf 6缺陷的斑马鱼模型，也显示出加速发育动力学后减少phf 6或notch 1激活。总之，我们的工作揭示了PHF 6表达的适当控制对于正常的人类造血是重要的，并为PHF 6在T-ALL发展中的作用提供了线索。
Transcriptional control of hematopoiesis involves complex regulatory networks and functional perturbations in one of these components often results in malignancies. Loss-of-function mutations in PHF6, encoding a presumed epigenetic regulator, have been primarily described in T cell acute lymphoblastic leukemia (T-ALL) and the first insights into its function in normal hematopoiesis only recently emerged from mouse modeling experiments. Here, we investigated the role of PHF6 in human blood cell development by performing knockdown studies in cord blood and thymus-derived hematopoietic precursors to evaluate the impact on lineage differentiation in well-established in vitro models. Our findings reveal that PHF6 levels differentially impact the differentiation of human hematopoietic progenitor cells into various blood cell lineages, with prominent effects on lymphoid and erythroid differentiation. We show that loss of PHF6 results in accelerated human T cell development through reduced expression of NOTCH1 and its downstream target genes. This functional interaction in developing thymocytes was confirmed in vivo using a phf6-deficient zebrafish model that also displayed accelerated developmental kinetics upon reduced phf6 or notch1 activation. In summary, our work reveals that appropriate control of PHF6 expression is important for normal human hematopoiesis and provides clues towards the role of PHF6 in T-ALL development.
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成人 T 细胞急性淋巴细胞白血病中 PHF6 和 NOTCH1 突变共存。
影响因子：
2.9
作者：
Li M;Xiao L;Xu J;Zhang R;Guo J;Olson J;Wu Y;Li J;Song C;Ge Z
通讯作者：
Ge Z
影响因子：
3.2
作者：
Chiang MY;Radojcic V;Maillard I
通讯作者：
Maillard I
影响因子：
16.6
作者：
Gama-Norton L;Ferrando E;Ruiz-Herguido C;Liu Z;Guiu J;Islam AB;Lee SU;Yan M;Guidos CJ;López-Bigas N;Maeda T;Espinosa L;Kopan R;Bigas A
通讯作者：
Bigas A
影响因子：
32.4
作者：
Ciofani, Maria;Knowles, Gisele C.;Zuniga-Pflucker, Juan Carlos
通讯作者：
Zuniga-Pflucker, Juan Carlos
影响因子：
30.5
作者：
Casero D;Sandoval S;Seet CS;Scholes J;Zhu Y;Ha VL;Luong A;Parekh C;Crooks GM
通讯作者：
Crooks GM