Systems Biology of Megakaryocytes

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.

Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing

“…RUNX1, GATA1, STAT5A and TAL1(SCL) are well-studied transcription factors for their roles in MK differentiation ( Crispino, 2005 ; Olthof et al, 2008 ; Tijssen et al, 2011 ). Signal transduction genes important for hematopoiesis such as RPTOR and CDC42 ( Kaushansky and Kaushansky, 2014 ) were found on the list as well. Therefore, RBM15 protein level may affect hematopoiesis via multiple pathways.…”

Nobiletin Promotes Megakaryocytic Differentiation through the MAPK/ERK-Dependent EGR1 Expression and Exerts Anti-Leukemic Effects in Human Chronic Myeloid Leukemia (CML) K562 Cells

“…Megakaryocytic differentiation is an orchestrated signaling cascade that pushes cells toward cellular enlargement and polyploidization, expression of cell type-specific markers, including CD61, CD41, CD42, and other changes [11]. However, only a few transcription factors have been reported to be involved in this process, such as EGR1, GATA-1, and RUNX1 [12,13]. Previous studies of phorbol 12-myristate 13-acetate (PMA) have led to a greater understanding of the regulatory networks that participate in megakaryocytic differentiation.…”

Identification of DNA methylation prognostic signature of acute myelocytic leukemia

“…Regulatory associated protein of MTOR complex 1 ( RPTOR ) is a signal transduction gene important for hematopoiesis [ 28 ]. RPTOR , mechanistic target of rapamycin kinase and MTOR associated protein (mTOR), LST8 homolog (MLST8) constitute the core subunits of the mammalian TORC1 complex which play an important role in controlling cell growth, survival and metabolism and is often deregulated in cancer [ 29 – 32 ].…”