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A Systems Biology Approach to Blood pp 59–84Cite as

Systems Biology of Megakaryocytes

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 844))

Abstract

The molecular pathways that regulate megakaryocyte production have historically been identified through multiple candidate gene approaches. Several transcription factors critical for generating megakaryocytes were identified by promoter analysis of megakaryocyte-specific genes, and their biological roles then verified by gene knockout studies; for example, GATA-1, NF-E2, and RUNX1 were identified in this way. In contrast, other transcription factors important for megakaryopoiesis were discovered through a systems approach; for example, c-Myb was found to be critical for the erythroid versus megakaryocyte lineage decision by genome-wide loss-of-function studies. The regulation of the levels of these transcription factors is, for the most part, cell intrinsic, although that assumption has recently been challenged. Epigenetics also impacts megakaryocyte gene expression, mediated by histone acetylation and methylation. Several cytokines have been identified to regulate megakaryocyte survival, proliferation, and differentiation, most prominent of which is thrombopoietin. Upon binding to its receptor, the product of the c-Mpl proto-oncogene, thrombopoietin induces a conformational change that activates a number of secondary messengers that promote cell survival, proliferation, and differentiation, and down-modulate receptor signaling. Among the best studied are the signal transducers and activators of transcription (STAT) proteins; phosphoinositol-3-kinase; mitogen-activated protein kinases; the phosphatases PTEN, SHP1, SHP2, and SHIP1; and the suppressors of cytokine signaling (SOCS) proteins. Additional signals activated by these secondary mediators include mammalian target of rapamycin; β(beta)-catenin; the G proteins Rac1, Rho, and CDC42; several transcription factors, including hypoxia-inducible factor 1α(alpha), the homeobox-containing proteins HOXB4 and HOXA9, and a number of signaling mediators that are reduced, including glycogen synthase kinase 3α(alpha) and the FOXO3 family of forkhead proteins. More recently, systematic interrogation of several aspects of megakaryocyte formation have been conducted, employing genomics, proteomics, and chromatin immunoprecipitation (ChIP) analyses, among others, and have yielded many previously unappreciated signaling mechanisms that regulate megakaryocyte lineage determination, proliferation, and differentiation. This chapter focuses on these pathways in normal and neoplastic megakaryopoiesis, and suggests areas that are ripe for further study.

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Authors and Affiliations

  1. Malaria Program, Seattle Biomedical Research Institute, 307 Westlake Ave., North, Suite 500, 98109, Seattle, WA, USA

    Alexis Kaushansky PhD

  2. Office of the Sr. Vice President, Health Sciences, Stony Brook Medicine, Health Sciences Tower, Level 4, Room 255, 11794-8430, Stony Brook, NY, USA

    Kenneth Kaushansky MD

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Correspondence to Kenneth Kaushansky MD .

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Editors and Affiliations

  1. Departments of Pediatrics and Cell & Molecular Biology, Northwestern University Feinberg School of Medicine and Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA

    Seth Joel Corey

  2. Department of Statistics, Rice University, Houston, Texas, USA

    Marek Kimmel

  3. Northwestern University Comprehensive Cancer Center, Evanston, Illinois, USA

    Joshua N. Leonard

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Kaushansky, A., Kaushansky, K. (2014). Systems Biology of Megakaryocytes. In: Corey, S., Kimmel, M., Leonard, J. (eds) A Systems Biology Approach to Blood. Advances in Experimental Medicine and Biology, vol 844. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2095-2_4

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