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Blood, 19 February 2009, Vol. 113, No. 8, pp. 1778-1785. Prepublished online as a Blood First Edition Paper on September 16, 2008; DOI 10.1182/blood-2007-11-124859. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-11-124859v1 113/8/1778    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 Lannutti, B. J. Articles by Josephson, N. C. Search for Related Content PubMed PubMed Citation Articles by Lannutti, B. J. Articles by Josephson, N. C. Related Collections Hematopoiesis and Stem Cells Platelets and Thrombopoiesis Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLATELETS AND THROMBOPOIESIS Incomplete restoration of Mpl expression in the mpl–/– mouse produces partial correction of the stem cell–repopulating defect and paradoxical thrombocytosis Brian J. Lannutti1,2, Angela Epp1, Jacqueline Roy1, Junmei Chen1, and Neil C. Josephson1,2 1 Puget Sound Blood Center, Seattle, WA; and 2 Department of Medicine, Division of Hematology, University of Washington, Seattle Expression of Mpl is restricted to hematopoietic cells in the megakaryocyte lineage and to undifferentiated progenitors, where it initiates critical cell survival and proliferation signals after stimulation by its ligand, thrombopoietin (TPO). As a result, a deficiency in Mpl function in patients with congenital amegakaryocytic thrombocytopenia (CAMT) and in mpl–/– mice produces profound thrombocytopenia and a severe stem cell–repopulating defect. Gene therapy has the potential to correct the hematopoietic defects of CAMT by ectopic gene expression that restores normal Mpl receptor activity. We rescued the mpl–/– mouse with a transgenic vector expressing mpl from the promoter elements of the 2-kb region of DNA just proximal to the natural gene start site. Transgene rescued mice exhibit thrombocytosis but only partial correction of the stem cell defect. Furthermore, they show very low-level expression of Mpl on platelets and megakaryocytes, and the transgene-rescued megakaryocytes exhibit diminished TPO-dependent kinase phosphorylation and reduced platelet production in bone marrow chimeras. Thrombocytosis is an unexpected consequence of reduced Mpl expression and activity. However, impaired TPO homeostasis in the transgene-rescued mice produces elevated plasma TPO levels, which serves as an unchecked stimulus to drive the observed excessive megakaryocytopoiesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Mpl and thrombocytosis: levels matter Stefan N. Constantinescu Blood 2009 113: 1617-1618. [Full Text] [PDF] This article has been cited by other articles: J. R. Lambert, T. Everington, D. C. Linch, and R. E. Gale In essential thrombocythemia, multiple JAK2-V617F clones are present in most mutant-positive patients: a new disease paradigm Blood, October 1, 2009; 114(14): 3018 - 3023. [Abstract] [Full Text] [PDF] S. N. Constantinescu Mpl and thrombocytosis: levels matter Blood, February 19, 2009; 113(8): 1617 - 1618. [Full Text] [PDF]

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