Stat5 is indispensable for the maintenance of bcr/abl‐positive leukaemia

A Hoelbl, C Schuster, B Kovacic, B Zhu… - EMBO molecular …, 2010 - embopress.org
A Hoelbl, C Schuster, B Kovacic, B Zhu, M Wickre, MA Hoelzl, S Fajmann, F Grebien
EMBO molecular medicine, 2010embopress.org
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 …
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 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).
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