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Stat5 is indispensable for the maintenance of <i>bcr/abl</i> -positive leukaemia
Hoelbl, Andrea,Schuster, Christian,Kovacic, Boris,Zhu, Bingmei,Wickre, Mark,Hoelzl, Maria A,Fajmann, Sabine,Grebien, Florian,Warsch, Wolfgang,Stengl, Gabriele,Hennighausen, Lothar,Poli, Valeria,Beug, WILEY-VCH Verlag 2010 EMBO molecular medicine Vol.2 No.3
<P>Tumourigenesis caused by the Bcr/Abl oncoprotein is a multi-step process proceeding from initial to tumour-maintaining events and finally results in a complex tumour-supporting network. A key to successful cancer therapy is the identification of critical functional nodes in an oncogenic network required for disease maintenance. So far, the transcription factors Stat3 and Stat5a/b have been implicated in <I>bcr/abl</I>-induced initial transformation. However, to qualify as a potential drug target, a signalling pathway must be required for the maintenance of the leukaemic state. Data on the roles of Stat3 or Stat5a/b in leukaemia maintenance are elusive. Here, we show that both, Stat3 and Stat5 are necessary for initial transformation. However, Stat5- but not Stat3-deletion induces G<SUB>0</SUB>/G<SUB>1</SUB> cell cycle arrest and apoptosis of imatinib-sensitive and imatinib-resistant stable leukaemic cells <I>in vitro</I>. Accordingly, Stat5-abrogation led to effective elimination of myeloid and lymphoid leukaemia maintenance <I>in vivo</I>. Hence, we identified Stat5 as a vulnerable point in the oncogenic network downstream of Bcr/Abl representing a case of non-oncogene addiction (NOA).</P>