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Transcriptional Control of Megakaryocyte Development Oncogene (2007) 26, 6795–6802 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Transcriptional control of megakaryocyte development AN Goldfarb Department of Pathology, University of Virginia School of Medicine, VA, USA Megakaryocytes are highly specialized cells that arise and erythroblasts represents probably the most striking from a bipotent megakaryocytic-erythroid progenitor example of sibling divergence in developmental biology. (MEP). This developmental leap requires coordinated acti- Megakaryocytes pursue a ‘hypertrophic’ pathway, en- vation of megakaryocyte-specific genes, radical changes in compassing vast cellular enlargement, acquisition of cell cycle properties, and active prevention of erythroid polyploidy and the elaboration of several unique differentiation. These programs result from upregulation cytoplasmic membranous structures. Erythroblasts opt of megakaryocyte-selective transcription factors, down- for an ‘atrophic’ pathway characterized by cellular regulation of erythroid-selective transcription factors and shrinkage, cytoplasmic simplification with jettisoning ongoing mediation of common erythro-megakaryocytic of several organelles, and a highly focused, almost transcription factors. Unlike most developmental pro- single-minded, gene expression program. Underlying grams, no single lineage-unique family of master regula- this phenotypic divergence lies an array of transcription tors exerts executive control over the megakaryocytic factors, some of which are restricted to either lineage, plan. Rather, an assemblage of non-unique factors and but many of which are shared by both lineages signals converge to determine lineage and differentiation. (Figure 1). Further complicating this picture, most of In human megakaryopoiesis, hereditary disorders of these transcription factors subsume multiple tasks, platelet production have confirmed contributions from repressing or activating a repertoire of target genes that three distinct transcription factor families. Murine models shifts as a function of lineage and stage. have extended this repertoire to include multiple addi- Insights into individual players in this process have tional factors. At a mechanistic level, the means by which been gained from comparisons of megakaryocytic and these non-unique factors collaborate in the establishment erythroid promoter/enhancers, from identification of of a perfectly unique cell type remains a central question. genetic defects in human hereditary disorders of Oncogene (2007) 26, 6795–6802; doi:10.1038/sj.onc.1210762 megakaryopoiesis and from mouse genetics, both targeted and random. The major challenge consists of Keywords: megakaryocyte; platelet; development; tran- developing and validating an integrated model for the scription factor cooperative function of these various factors as they collaborate in programming megakaryopoiesis. Discordant offspring from a mutually endearing parent GATA and Friend in sickness and in health: X-linked (MEP): erythro-megakaryocytic divergence thrombocytopenia Megakaryocytic differentiation begins with the bipotent A canonical feature of megakaryocytic promoters is the megakaryocytic-erythroid progenitor (MEP), an entity presence of binding sites for the GATA family of zinc- whose existence was inferred from in vitro clonal finger transcription factors: WGATAR. Clinical rele- hematopoietic differentiation assays (Debili et al., vance for one of these sites is illustrated in a patient with 1996) and confirmed through prospective cellular isola- Bernard–Soulier syndrome (macrothrombocytopenia, tion (Akashi et al., 2000; Manz et al., 2002). The MEP decreased platelet expression of the gpI-IX-V complex may arise from either a committed common myeloid and decreased platelet aggregation in response to risto- progenitor (CMP) (Akashi et al., 2000) or directly from cetin) in whoma GATA binding site within the glycopro- a more primitive, uncommitted short-term hematopoie- tein Ibb promoter underwent mutation (Ludlow et al., tic stemcell (ST-HSC) (Adolfsson et al., 2005), by an 1996). GATA-1 and GATA-2 represent the major unknown mechanism that may involve programming by GATA proteins expressed during erythro-megakaryo- the transcription factor GATA-1 (Stachura et al., 2006). cytic differentiation, with GATA-1 levels increasing and The further development of MEP into megakaryocytes GATA-2 levels decreasing during the differentiation of both lineages (Cantor and Orkin, 2002). Coexpressed with these GATA factors is FOG1, a large multifinger Correspondence: Dr AN Goldfarb, University of Virginia Health Sciences Center, Box 800904, Charlottesville, Virginia, VA 22908, protein serving as a dedicated GATA coregulator. USA. Mouse knockouts have implicated GATA-1 and E-mail: [email protected] FOG1 specifically in erythroid and megakaryocytic Transcription in megakaryopoiesis AN Goldfarb 6796 EKLF c-Myb p300 Mediator (?) Ery Early Late GATA-2/FOG1 GATA-1/FOG1 NF-E2 SCL LMO2 GFI-1b Mk GABP Fli-1 RUNX1 Figure 1 Diagram of transcription factors involved in lineage divergence from a common megakaryocyte-erythroid progenitor. The factors are organized on the y-axis according to degree of lineage selectivity. For example, RUNX1 and EKLF represent highly selective megakaryocytic and erythroid factors, respectively. In the middle are factors equally involved in both lineages, such as GATA-1 and FOG1. Orientation on the x-axis reflects the stage of differentiation in which the factors are involved. For example c-Myb most likely participates in early erythroid commitment of the MEP, whereas NF-E2 contributes to later development of both lineages. This diagram does not reflect the dual roles of some factors in early and late stages of differentiation, as may occur with RUNX1. development; GATA-2 by contrast contributes to the associated with moderate to severe thrombocytopenia in proliferation of multipotent progenitors (Cantor and the absence of anemia, but the more structurally Orkin, 2002). disruptive substitution D218Y resulted in severe throm- Experiments of nature have provided glimpses of the bocytopenia and anemia, again suggesting that mega- role of GATA-1 in human megakaryopoiesis. As many karyopoiesis is more sensitive than erythropoiesis to as four distinct biochemical classes of GATA-1 muta- diminished GATA-1 function (Freson et al., 2001, tion have been found in human X-linked disorders of 2002). The single kindred identified with a mutation megakaryocyte development (Liew et al., 2005). The causing GATA-1s surprisingly displayed macrocytic first class of mutations comprises N finger amino acid anemia with normal platelet counts; however, platelet substitutions which impair FOG1 binding, two exam- morphology and function were abnormal (Hollanda ples of which have been reported: V205M and G208S et al., 2006). A fascinating feature shared by various (Nichols et al., 2000; Mehaffey et al., 2001). The second kindreds with GATA-1 mutations is a role reversal in the class involves N-finger substitutions which preserve erythro-megakaryocytic divergence, the erythroblasts FOG1 binding but impair binding to a DNA GATC showing enlargement with multinucleation and the motif found within paired GATA target sites: examples megakaryocytes developing as small cells with hypolo- are R216Q and R216W (Yu et al., 2002; Phillips et al., bulated nuclei, ‘micromegakaryocytes’ (Nichols et al., 2007). The third class also affects the N finger but 2000; Freson et al., 2001, 2002; Hollanda et al., 2006; disrupts neither FOG1 nor DNA binding: D218G Phillips et al., 2007). (Freson et al., 2001; Liew et al., 2005). The biochemical Multiple themes emerge from a survey of the human defect in this third class thus remains mysterious. An and murine GATA-1 mutant phenotypes: (1) GATA-1 interaction potentially affected by this, or other, N-finger plays crucial roles in both megakaryopoiesis and erythro- substitutions could be the recently described binding of poiesis, roles that cannot be fulfilled by GATA-2 despite the mediator complex to the GATA-1 N finger (Stumpf structural and biochemical similarities; (2) distinct et al., 2006). The fourth class of hereditary GATA-1 structural elements within GATA-1 contribute to mutation causes congenital expression of GATA-1s, an distinct aspects of the differentiation program, a finding amino terminally truncated form lacking the first 83 confirmed in ex vivo megakaryocytic rescue assays (Kuhl amino acids (Hollanda et al., 2006). et al., 2005; Muntean and Crispino, 2005); (3) mega- The disease phenotypes reveal influences fromboth karyopoiesis depends more on GATA-1 dosage than the site of substitution and the severity of loss of does erythropoiesis, a finding also supported by ex vivo biochemical function. As an example of the latter rescue assays (Stachura et al., 2006); (4) proper influence, megakaryopoiesis displays greater sensitivity segregation of the ‘hypertrophic’ and ‘atrophic’ pheno- than erythropoiesis to decrements in GATA-1 binding types during erythromegakaryocytic divergence relies on to FOG1. In particular, the V205M mutant shows the activity of GATA-1. greater loss of FOG1 binding than G208S, and patients with V205M have severe anemia and thrombocytopenia, whereas those with G208S have only severe thrombo- cytopenia with no anemia. As an example of the site At the core of megakaryopoiesis: RUNX1 and familial influence, substitutions of R216 affecting DNA binding platelet disorder (FPD/AML) produce moderate thrombocytopenia associated with a thalassemic
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