Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
Blood. 2011 Jul 21;118(3):723-35. doi: 10.1182/blood-2011-01-328765. Epub 2011 May 19.
Megakaryopoiesis is a complex process that involves major cellular and nuclear changes and relies on controlled coordination of cellular proliferation and differentiation. These mechanisms are orchestrated in part by transcriptional regulators. The key hematopoietic transcription factor stem cell leukemia (SCL)/TAL1 is required in early hematopoietic progenitors for specification of the megakaryocytic lineage. These early functions have, so far, prevented full investigation of its role in megakaryocyte development in loss-of-function studies. Here, we report that SCL critically controls terminal megakaryocyte maturation. In vivo deletion of Scl specifically in the megakaryocytic lineage affects all key attributes of megakaryocyte progenitors (MkPs), namely, proliferation, ploidization, cytoplasmic maturation, and platelet release. Genome-wide expression analysis reveals increased expression of the cell-cycle regulator p21 in Scl-deleted MkPs. Importantly, p21 knockdown-mediated rescue of Scl-mutant MkPs shows full restoration of cell-cycle progression and partial rescue of the nuclear and cytoplasmic maturation defects. Therefore, SCL-mediated transcriptional control of p21 is essential for terminal maturation of MkPs. Our study provides a mechanistic link between a major hematopoietic transcriptional regulator, cell-cycle progression, and megakaryocytic differentiation.
巨核细胞生成是一个复杂的过程，涉及主要的细胞和核变化，并依赖于细胞增殖和分化的受控协调。这些机制部分由转录调节剂来协调。关键的造血转录因子 stem cell leukemia (SCL)/TAL1 在早期造血祖细胞中对于巨核细胞谱系的特化是必需的。这些早期功能迄今为止阻止了在功能丧失研究中对其在巨核细胞发育中的作用进行全面研究。在这里，我们报告 SCL 严格控制着巨核细胞的终末成熟。在巨核细胞谱系中特异性缺失 Scl 会影响巨核细胞祖细胞（MkP）的所有关键属性，即增殖、倍性化、细胞质成熟和血小板释放。全基因组表达分析显示 Scl 缺失的 MkP 中细胞周期调节剂 p21 的表达增加。重要的是，p21 敲低介导的 Scl 突变 MkP 的挽救显示出细胞周期进程的完全恢复和核和细胞质成熟缺陷的部分挽救。因此，SCL 介导的 p21 的转录控制对于 MkP 的终末成熟是必需的。我们的研究为主要的造血转录调节剂、细胞周期进展和巨核细胞分化之间提供了一个机制联系。
