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Blood, 15 October 2008, Vol. 112, No. 8, pp. 3434-3443. Prepublished online as a Blood First Edition Paper on May 12, 2008; DOI 10.1182/blood-2008-02-139824. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2008-02-139824v1 112/8/3434    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 CrossRef Google Scholar Articles by Zhou, L. Articles by Verma, A. PubMed PubMed Citation Articles by Zhou, L. Articles by Verma, A. Related Collections Neoplasia Red Cells Chemokines, Cytokines, and Interleukins Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS Li Zhou1, Aaron N. Nguyen2, Davendra Sohal1, Jing Ying Ma2, Perry Pahanish1,3, Krishna Gundabolu1, Josh Hayman1, Adam Chubak1, Yongkai Mo1, Tushar D. Bhagat1, Bhaskar Das1, Ann M. Kapoun2, Tony A. Navas2, Simrit Parmar3, Suman Kambhampati4, Andrea Pellagatti5, Ira Braunchweig1, Ying Zhang6, Amittha Wickrema7, Satyanarayana Medicherla2, Jacqueline Boultwood5, Leonidas C. Platanias8, Linda S. Higgins2, Alan F. List9, Markus Bitzer1, and Amit Verma1,3 1 Albert Einstein College of Medicine, Bronx, NY; 2 Scios, Fremont, CA; 3 University of Texas Southwestern Medical School and Dallas Veterans Affairs Medical Center (VAMC); 4 VAMC, Kansas City, MO; 5 John Radcliffe Hospital, Oxford, United Kingdom; 6 Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, MD; 7 University of Chicago, IL; 8 Northwestern University Robert H. Lurie Cancer Center, Chicago, IL; and 9 Moffitt Cancer Center, Tampa, FL MDS is characterized by ineffective hematopoiesis that leads to peripheral cytopenias. Development of effective treatments has been impeded by limited insight into pathogenic pathways governing dysplastic growth of hematopoietic progenitors. We demonstrate that smad2, a downstream mediator of transforming growth factor–β (TGF-β) receptor I kinase (TBRI) activation, is constitutively activated in MDS bone marrow (BM) precursors and is overexpressed in gene expression profiles of MDS CD34+ cells, providing direct evidence of overactivation of TGF-β pathway in this disease. Suppression of the TGF-β signaling by lentiviral shRNA-mediated down-regulation of TBRI leads to in vitro enhancement of hematopoiesis in MDS progenitors. Pharmacologic inhibition of TBRI (alk5) kinase by a small molecule inhibitor, SD-208, inhibits smad2 activation in hematopoietic progenitors, suppresses TGF-β–mediated gene activation in BM stromal cells, and reverses TGF-β–mediated cell-cycle arrest in BM CD34+ cells. Furthermore, SD-208 treatment alleviates anemia and stimulates hematopoiesis in vivo in a novel murine model of bone marrow failure generated by constitutive hepatic expression of TGF-β1. Moreover, in vitro pharmacologic inhibition of TBRI kinase leads to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF-β signaling in the pathobiology of ineffective hematopoiesis and identify TBRI as a potential therapeutic target in low-risk MDS. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Unlocking the dysplasia puzzle Camille N. Abboud Blood 2008 112: 3005-3006. [Full Text] [PDF]

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