title: Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia.
abstract: 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 G(0)/G(1) 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).
authors.affiliation: Institute of Pharmacology, Centre of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hoelbl
authors.forename: Christian
authors.initials: C
authors.lastname: Schuster
authors.forename: Boris
authors.initials: B
authors.lastname: Kovacic
authors.forename: Bingmei
authors.initials: B
authors.lastname: Zhu
authors.forename: Mark
authors.initials: M
authors.lastname: Wickre
authors.forename: Maria A
authors.initials: MA
authors.lastname: Hoelzl
authors.forename: Sabine
authors.initials: S
authors.lastname: Fajmann
authors.forename: Florian
authors.initials: F
authors.lastname: Grebien
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Warsch
authors.forename: Gabriele
authors.initials: G
authors.lastname: Stengl
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
authors.forename: Valeria
authors.initials: V
authors.lastname: Poli
authors.forename: Hartmut
authors.initials: H
authors.lastname: Beug
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D017353:Gene Deletion; D016313:Genes, abl; D007938:Leukemia / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr