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Blood, 15 October 2008, Vol. 112, No. 8, pp. 3148-3153. Prepublished online as a Blood First Edition Paper on August 6, 2008; DOI 10.1182/blood-2007-10-119677. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-10-119677v1 112/8/3148    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kauppi, M. Articles by Alexander, W. S. Search for Related Content PubMed PubMed Citation Articles by Kauppi, M. Articles by Alexander, W. S. Related Collections Hematopoiesis and Stem Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS Point mutation in the gene encoding p300 suppresses thrombocytopenia in Mpl–/– mice Maria Kauppi1,*, James M. Murphy2,*, Carolyn A. de Graaf2,3, Craig D. Hyland1, Kylie T. Greig2,3, Donald Metcalf1, Adrienne A. Hilton1, Nicos A. Nicola1, Benjamin T. Kile2, Douglas J. Hilton2, and Warren S. Alexander1 1 Cancer and Haematology and 2 Molecular Medicine Divisions, The Walter and Eliza Hall Institute of Medical Research, Parkville; and 3 Department of Medical Biology, The University of Melbourne, Parkville, Australia In an N-nitroso-N-ethylurea (ENU) mutagenesis screen using Mpl–/– mice, we isolated a semidominant suppressor of thrombocytopenia, termed Plt6. The gene mutated in Plt6 mice encodes the transcriptional coregulator p300, and the mutation, a tyrosine to asparagine substitution at amino acid 630 (Y630N), disrupts the interaction between p300 and c-Myb. Mpl–/– p300Plt6/+ mice displayed elevated platelet counts relative to Mpl–/– p300+/+ controls, whereas mice homozygous for the Plt6 mutation produced supraphysiological levels of circulating platelets. On a wild-type genetic background, mice homozygous for the p300Plt6 mutation, or recipients of Mpl+/+ p300Plt6/Plt6 bone marrow, also exhibited thrombocytosis as well as deficiencies in B-lymphoid cells. Increased platelet numbers in Plt6 mutant mice were accompanied by significant increases in megakaryocyte progenitor cells within the bone marrow and spleen with concomitantly elevated numbers of megakaryocytes. The expansion of megakaryocytopoiesis and suppression of Mpl–/– thrombocytopenia in Plt6 mutants is highly reminiscent of that observed in mice with mutations affecting the p300 partner protein c-Myb, suggesting an indispensable repressive role for the c-Myb/p300 transcriptional regulatory complex in megakaryocyte develop-ment, the inhibition of which allows substantial thrombopoietin (TPO)–independent platelet production. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. R. Pattabiraman, J. Sun, D. H. Dowhan, S. Ishii, and T. J. Gonda Mutations in Multiple Domains of c-Myb Disrupt Interaction with CBP/p300 and Abrogate Myeloid Transforming Ability Mol. Cancer Res., September 1, 2009; 7(9): 1477 - 1486. [Abstract] [Full Text] [PDF] D. J. Hilton, B. T. Kile, and W. S. Alexander Mutational inhibition of c-Myb or p300 ameliorates treatment-induced thrombocytopenia Blood, May 28, 2009; 113(22): 5599 - 5604. [Abstract] [Full Text] [PDF]

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