Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia.
Hoelbl, Andrea 1; Schuster, Christian 1,7; Kovacic, Boris 2; Zhu, Bingmei 3; Wickre, Mark 3; Hoelzl, Maria A. 1; Fajmann, Sabine 1; Grebien, Florian 4,8; Warsch, Wolfgang 1; Stengl, Gabriele 2; Hennighausen, Lothar 3; Poli, Valeria 5; Beug, Hartmut 2; Moriggl, Richard 6; Sexl, Veronika 1,*
[Article]
Embo Molecular Medicine.
2(3):98-110, March 2010.
(Format: HTML, PDF)
: 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 bcr/abl-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 G0/G1 cell cycle arrest and apoptosis of imatinib-sensitive and imatinib-resistant stable leukaemic cells in vitro. Accordingly, Stat5-abrogation led to effective elimination of myeloid and lymphoid leukaemia maintenance in vivo. Hence, we identified Stat5 as a vulnerable point in the oncogenic network downstream of Bcr/Abl representing a case of non-oncogene addiction (NOA).
Copyright (C) 2010 John Wiley & Sons, Inc.