IntroductionStat molecules are part of a highly conserved signaling pathway involved in cell-fate decisions like differentiation, proliferation, and apoptosis. [1][2][3] The cytokines interleukin-2, -4, and -7 (IL-2, IL-4, IL-7) regulate important aspects of lymphoid development and are strong activators of the transcription factors Stat5a and Stat5b. 4 The importance of Stat5a/b for lymphoid cells is also underlined by the fact that constitutively activated Stat5a/b are found in several forms of lymphoid leukemia in mice and humans. [5][6][7][8][9][10] Gene knockouts have greatly contributed to our knowledge about Stat transcription factors because they allowed exploration of their physiologic and pathophysiologic functions. 11 So far, all studies investigating the role of Stat5a/b in lymphopoiesis employed gene-targeted mice still expressing a residual protein corresponding to an N-terminal deletion mutant (Stat5a/b⌬N). 4,[12][13][14] Stat5a/b ⌬N/⌬N mice revealed surprisingly mild phenotypes in Band T-cell development and function.Characterization of the lymphoid compartment in Stat5a/b ⌬N/⌬N mice showed a modest reduction of B-and T-lymphoid-cell numbers accompanied by a complete lack of natural killer (NK) cells and CD4 ϩ CD25 ϩ suppressor T cells. 4,13,15 CD8 ϩ T cells were present but failed to respond to ␣-CD3 and IL-2. 4 Mature B-cell numbers in the periphery were also reduced due to an incomplete block at the early pro-B-cell developmental stage (Hardy fraction B). 13,14 Mice lacking IL-7 or the IL-7R have a block at the earliest step of B-cell development at Hardy fraction A and lack mature B-lymphoid cells in the periphery. 16,17 Notably, B-cell development can be rescued in these mice by forced expression of a constitutively active Stat5a/b mutant. 17 In addition, transgenic mice expressing a constitutively active Stat5b (Stat5b-CA) have increased numbers of pro-B cells. 14 As Stat5a/b are critical components in the signaling cascade downstream of IL-7R, abrogation of Stat5a/b was predicted to result in a dramatic phenotype. Thus, the observations in Stat5a/b ⌬N/⌬N mice were difficult to reconcile with the current understanding of signaling pathways controlling B-cell development.Moreover, Stat5a/b transcription factors have been shown to play an important role in various T-cell developmental decisions. Transgenic Stat5b-CA mice display increased numbers of CD8 ϩ but not CD4 ϩ T cells. 18 This implicates Stat5b as an important regulator of CD4 ϩ /CD8 ϩ lineage decision. Moreover, Stat5a/b DNA binding sites were found in regulatory regions of the T-cell receptor ␥ (TCR␥) gene locus, and Stat5b-CA mice displayed a modest increase in ␥␦ T-cell numbers. 18,19 In Stat5a/b ⌬N/⌬N mice, embryonic ␥␦ T-cell development was severely affected, but numbers were rapidly restored after birth. 20 Therefore, the relevance for Stat5a/b in adult ␥␦ thymopoiesis remained elusive. Another finding in Stat5a/b ⌬N/⌬N mice was striking. Among many substrates that are phosphorylated downstream of the Abelson oncogene, Stat5a...

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).