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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 (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 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 Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 19, 2008 Accepted April 14, 2008 Inhibition of the TGF- receptor I kinase promotes hematopoiesis in MDS Li Zhou, Aaron N Nguyen, Davendra Sohal, Jing Ying Ma, Perry Pahanish, Krishna Gundabolu, Josh Hayman, Adam Chubak, Yongkai Mo, Tushar Bhagat, Bhaskar Das, Ann M Kapoun, Tony A Navas, Simrit Parmar, Suman Kambhampati, Andrea Pellagatti, Ira Braunschweig, Ying Zhang, Amittha Wickrema, Satyanarayana Medicherla, Jacqueline Boultwood, Leonidas C Platanias, Linda S Higgins, Alan F List, Markus Bitzer, and Amit Verma* Medicine, Albert Einstein College of Medicine, Bronx, NY, United States Scios, Scios Inc, Fremont, CA, United States Medicine, Dallas VAMC, University of Texas Southwestern, Dallas, TX, United States Medicine, Kansas City VAMC, Kansas City, MO, United States Oncology, John Radcliffe Hospital, Oxford, United Kingdom Oncology, Albert Einstein College of Medicine, Bronx, NY, United States Laboratory of Cellular & Molecular Biology, National Cancer Institute, Bethesda, MD, United States Oncology, University of Chicago, Chicago, IL, United States Cancer Center, Northwestern University, Chicago, IL, United States Hematologic Malignancies, Moffitt Cancer Center, Tampa, FL, United States * Corresponding author; email: averma{at}aecom.yu.edu. 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 TGF- 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- pathway in this disease. Suppression of the TGF- signaling by lentiviral shRNA mediated downregulation of TBRI leads to in vitro enhancement of hematopoiesis in MDS progenitors. Pharmacological inhibition of TBRI (alk5) kinase by a small molecule inhibitor, SD-208, inhibits smad2 activation in hematopoietic progenitors, suppresses TGF- mediated gene activation in BM stromal cells and reverses TGF- 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-1. Moreover, in vitro pharmacologic inhibition of TBRI kinase leads to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF- 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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