Megakaryocytic Fate Specification and Maturation

Megakaryocyte maturation and polyploidization are essential for effective platelet formation. In a tightly controlled process, bipotent megakaryocyte-erythroid progenitors (MEP) differentiate into diploid megakaryoblasts; undergo a progressive increase in ploidy, resulting in very large cells with multilobated polyploid nuclei; and undergo extensive cytoplasmic maturation in preparation for proplatelet release. Recent studies have begun to unravel the complex genetic and epigenetic changes that promote megakaryocyte specification from hematopoietic stem and progenitor cells, and that control subsequent megakaryocyte polyploidization and maturation. The transcriptional regulatory network underlying specification from MEP is emerging, with data revealing that many of the same factors that regulate specification also play critical roles in the final stages of megakaryocyte maturation, whereas other factors are critical for specification, but must be then inactivated in order for cell maturation to occur. Megakaryopoiesis is disrupted in several malignant and non-malignant disorders that result in significant morbidity and mortality. Mutations are inherited or acquired, and affect megakaryocyte specification, maturation and subsequent platelet formation, or both. Novel, findings will be covered in the context of normal transcriptional regulation, potential mechanisms of megakaryocyte dysplasia in MDS, and transformation to acute megakaryoblastic leukemia. These studies build the basis for our understanding of inherited and acquired megakaryocytic abnormalities and thrombocytopenias.