title: c-Myb and GATA-1 alternate dominant roles during megakaryocyte differentiation.
abstract: BACKGROUND
  Transcription factors are essential for blood cell formation. Mice expressing low levels of c-Myb (c-Myb(low)) have an increased number of bone marrow megakaryocytes (MKs) and corresponding thrombocytosis. In contrast, mice engineered to express low levels of GATA-1 (GATA-1(low)) in the megakaryocytic lineage exhibit aberrant megakaryocytopoiesis with hyperproliferation of progenitors and defective terminal differentiation leading to thrombocytopenia. These seemingly opposite roles may affect platelet turnover and thus be of clinical relevance.
  
  
  OBJECTIVE
  To determine how these two transcription factors act together to control megakaryocytopoiesis and platelet formation.
  
  
  METHODS
  We used a combination of cellular and molecular in vitro assays to examine the ability of bone marrow cells from mice expressing low levels of both c-Myb and GATA-1 (referred to as double(low)) to produce MKs and platelets.
  
  
  RESULTS
  Double(low) cells, or those with low GATA-1 levels in which c-Myb is conditionally deleted, lack the hyperproliferative capacity of GATA-1(low) cells, allowing the cells to proceed towards more committed MKs that are, however, impaired in their capacity to produce fully differentiated cells, as confirmed by the abundance of morphologically aberrant cells that lack the ability to form proplatelets.
  
  
  CONCLUSIONS
  c-Myb and GATA-1 act in concert to achieve correct megakaryocytic differentiation. GATA-1 regulates both the proliferation of megakaryocytic progenitors and their terminal maturation. c-Myb also acts at the level of the progenitor by influencing its commitment to differentiation, but in contrast to GATA-1 it does not have any effect on the process of terminal differentiation.
authors.affiliation: Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. p.garcia@bham.ac.uk
authors.forename: P
authors.initials: P
authors.lastname: García
authors.forename: O
authors.initials: O
authors.lastname: Berlanga
authors.forename: A
authors.initials: A
authors.lastname: Vegiopoulos
authors.forename: P
authors.initials: P
authors.lastname: Vyas
authors.forename: J
authors.initials: J
authors.lastname: Frampton
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D050982:GATA1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008533:Megakaryocytes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000235:genetics; D020598:Proto-Oncogene Proteins c-myb / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013921:Thrombocytopenia / Q000097:blood / Q000235:genetics; D013922:Thrombocytosis / Q000097:blood / Q000235:genetics; D034061:Thrombopoiesis
chemical_list: D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D020598:Proto-Oncogene Proteins c-myb