Molecular and Transcriptional Regulation of Megakaryocyte Differentiation

Abstract

Megakaryocytes, among the rarest of hematopoietic cells, serve the essential function of producing numerous platelets. Genetic studies have recently provided rich insights into the molecular and transcriptional regulation of megakaryocyte differentiation and thrombopoiesis. Three transcription factors, GATA-1, FOG-1, and NF-E2, are essential regulators of distinct stages in megakaryocyte differentiation, extending from the birth of early committed progenitors to the final step of platelet release; a fourth factor, Fli-1, likely also plays an important role. The putative transcriptional targets of these regulators, including the NF-E2-dependent hematopoietic-specific β-tubulin isoform β1, deepen our understanding of molecular mechanisms in platelet biogenesis. The study of rare syndromes of inherited thrombocytopenia in mice and man has also refined the emerging picture of megakaryocyte maturation. Synthesis of platelet-specific organelles is mediated by a variety of regulators of intracellular vesicle membrane fusion, and platelet release is coordinated through extensive and dynamic reorganization of the actin and microtubule cytoskeletons. As in other aspects of hematopoiesis, characterization of recurrent chromosomal translocations in human leukemias provides an added dimension to the molecular underpinnings of megakaryocyte differentiation. Long regarded as a mysterious cell, the megakaryocyte is thus yielding many of its secrets, and mechanisms of thrombopoiesis are becoming clearer. Although this review focuses on transcriptional control mechanisms, it also discusses recent advances in broader consideration of the birth of platelets.

p210BCR-ABL reprograms transformed and normal human megakaryocytic progenitor cells into erythroid cells and suppresses FLI-1 transcription

“…22,23 Furthermore, as revealed by gene targeting studies in mice, the development and differentiation of the erythroid and MK lineages are controlled by common transcription factors. [24][25][26] Among these transcription factors, FLI-1 (Friend leukemia integration 1) plays an essential role in both erythropoiesis and megakaryopoiesis. 27 In the present study, we report a novel mechanism whereby BCR-ABL overexpressing cells may undergo abnormal differentiation.…”

Overexpression of Ets-1 in human hematopoietic progenitor cells blocks erythroid and promotes megakaryocytic differentiation

“…12,13 In megakaryocytopoiesis Ets-1 is upregulated 14 and, Ets binding sites (EBS) have been identified in many megakaryocyte-specific gene promoters. 15 Only few studies, however, have examined its specific role in megakaryocytic (MK) differentiation.…”

Gene Expression Profile of Megakaryocytes from Human Cord Blood CD34+ Cells Ex Vivo Expanded by Thrombopoietin

“…Furthermore, nuclear factor (erythroid derived) 45 kD (4.75-fold higher expression in MKs) regulates two classes of gene expression in maturating MKs that are required to reorganize the MK cytoskeleton and initiate proplatelet formation [7]. cAMP-responsive element-binding protein-like 1, which is the binding partner of nuclear factor (erythroid derived) 45 kD, was also expressed highly in MKs (38-fold higher in MKs than in non-MKs).…”

“…Transcription factors, such as nuclear factor (erythroid-derived 2) 45 kD, nuclear factor (erythroid-derived 2)-like 2, and cAMP response element binding factor 2 were expressed more highly in MKs. These transcription factors may be important in the maturation of MKs [7]. Genes related in apoptotic event as well as in mitogen-activated protein kinase (MAPK) pathway were expressed more highly in MKs.…”