Warning: Undefined variable $zfal in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 525
Deprecated: str_replace(): Passing null to parameter #3 ($subject) of type array|string is deprecated in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 525
Warning: Undefined variable $sterm in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 530
free
Warning: Undefined variable $sterm in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 531
free free
Warning: file_get_contents(http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=18474728&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 445
English Wikipedia
Nephropedia Template TP (
Twit Text
DeepDyve Pubget Overpricing |
lüll Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS Zhou L; Nguyen AN; Sohal D; Ying Ma J; Pahanish P; Gundabolu K; Hayman J; Chubak A; Mo Y; Bhagat TD; Das B; Kapoun AM; Navas TA; Parmar S; Kambhampati S; Pellagatti A; Braunchweig I; Zhang Y; Wickrema A; Medicherla S; Boultwood J; Platanias LC; Higgins LS; List AF; Bitzer M; Verma ABlood 2008[Oct]; 112 (8): 3434-43MDS 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-beta (TGF-beta) 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-beta pathway in this disease. Suppression of the TGF-beta 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-beta-mediated gene activation in BM stromal cells, and reverses TGF-beta-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-beta1. Moreover, in vitro pharmacologic inhibition of TBRI kinase leads to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF-beta signaling in the pathobiology of ineffective hematopoiesis and identify TBRI as a potential therapeutic target in low-risk MDS.|*Hematopoiesis[MESH]|Aged[MESH]|Aged, 80 and over[MESH]|Animals[MESH]|Antigens, CD34/biosynthesis[MESH]|Bone Marrow/drug effects/pathology[MESH]|Female[MESH]|Humans[MESH]|Lentivirus/genetics[MESH]|Male[MESH]|Mice[MESH]|Mice, Transgenic[MESH]|Middle Aged[MESH]|Models, Biological[MESH]|Myelodysplastic Syndromes/*metabolism/*pathology[MESH]|Protein Serine-Threonine Kinases/*antagonists & inhibitors/metabolism[MESH]|Pteridines/pharmacology[MESH]|Receptor, Transforming Growth Factor-beta Type I[MESH]|Receptors, Transforming Growth Factor beta/*antagonists & inhibitors/metabolism[MESH] |