Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia.
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).
Hoelbl
Andrea
A
Institute of Pharmacology, Centre of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Austria.
Schuster
Christian
C
Kovacic
Boris
B
Zhu
Bingmei
B
Wickre
Mark
M
Hoelzl
Maria A
MA
Fajmann
Sabine
S
Grebien
Florian
F
Warsch
Wolfgang
W
Stengl
Gabriele
G
Hennighausen
Lothar
L
Poli
Valeria
V
Beug
Hartmut
H
Moriggl
Richard
R
Sexl
Veronika
V
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*
D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr