Abstract
Constitutive activation of STAT5 is critical for the maintenance of chronic myeloid leukemia (CML) characterized by the BCR-ABL oncoprotein. Tyrosine kinase inhibitors (TKIs) for the STAT5-activating kinase JAK2 have been discussed as a treatment option for CML patients. Using murine leukemia models combined with inducible ablation of JAK2, we show JAK2 dependence for initial lymphoid transformation, which is lost once leukemia is established. In contrast, initial myeloid transformation and leukemia maintenance were independent of JAK2. Nevertheless, several JAK2 TKIs induced apoptosis in BCR-ABL+ cells irrespective of the presence of JAK2. This is caused by the previously unknown direct 'off-target' inhibition of BCR-ABL. Cellular and enzymatic analyses suggest that BCR-ABL phosphorylates STAT5 directly. Our findings suggest uncoupling of the canonical JAK2-STAT5 module upon BCR-ABL expression, thereby making JAK2 targeting dispensable. Thus, attempts to pharmacologically target STAT5 in BCR-ABL+ diseases need to focus on STAT5 itself.
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Acknowledgements
This work was supported by grants WWTF-LS037 and SFB-28-10 to V.S. and GenAU-PLACEBO to G.S.-F. and V.S. We thank S. Georgeon for expert technical assistance. We thank all members of participating laboratories and R. Moriggl and T. Decker for continuous support and discussions.
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O.H. did the experiments in Figures 5d,e, 6b–f and 7. W.W. did the experiments in Figures 1, 2d,e, 3b–e, 4b–e, 5a–c,g and 6a. E.E. did the experiments in Figures 2a,b, 3a and 4a. I.K. provided technical assistance and vital tools for experiments in Figures 5d,e, 6b–f and 7. F.G. did the experiments in Figure 2c. K.-U.W. provided the conditional Jak2 knockout mice. G.S.-F. and V.S. designed the experiments and interpreted the data. O.H., W.W., G.S.-F. and V.S. wrote the manuscript.
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Hantschel, O., Warsch, W., Eckelhart, E. et al. BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia. Nat Chem Biol 8, 285–293 (2012). https://doi.org/10.1038/nchembio.775
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DOI: https://doi.org/10.1038/nchembio.775
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