Abstract
Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR–ABL1 (ref. 1) and other oncogenic tyrosine kinases2,3. Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases4,5. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs)6,7,8, which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones.
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Acknowledgements
We thank R. Dalla-Favera and L. Hennighausen for sharing BCL6−/− and STAT5fl/fl mice and wild-type controls with us. We thank A. L. Shaffer and L. M. Staudt for sharing their inducible BCL6 constructs. This work was supported by grants from the National Institutes of Health/National Cancer Institute through R01CA104348 (to A.M.), R01CA085573 (to B.H.Y.), R01CA026038 (to H.P.K.), R01CA090321 (to N.H.), R01CA137060 (to M.M.), R01CA139032 (to M.M.), R01CA157664 (to M.M.) and R21CA152497 (to M.M.), grants from the Leukemia and Lymphoma Society (to M.M.) Leukemia and Lymphoma Society SCOR 7005-11 (PI B. J. Druker), a grant from the Alex's Lemonade Stand Foundation for Pediatric Cancer Research (to M.M.), the California Institute for Regenerative Medicine through TR02-1816 (to M.M.), the William Laurence and Blanche Hughes Foundation and a Stand Up To Cancer-American Association for Cancer Research Innovative Research Grant IRG00909 (to M.M.). A.M. and M.M. are Scholars of the Leukemia and Lymphoma Society.
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C.D. and M.M. conceived the study and wrote the paper. M.M. and A.M. designed experiments and interpreted data. C.D., C.H., S. Shojaee, L.C., S. Swaminathan, L.K., S.-m.K, R.N., M.B., E.P. and Y.-m.K. designed and performed experiments and interpreted data. W.-K.H., H.P.K. and N.H. provided and characterized samples from patients. H.G. and T.G.G. analysed data. S.H., H.J., J.J.Y., H.W. and B.H.Y. provided important reagents and mouse samples.
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Duy, C., Hurtz, C., Shojaee, S. et al. BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR–ABL1 kinase inhibition. Nature 473, 384–388 (2011). https://doi.org/10.1038/nature09883
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DOI: https://doi.org/10.1038/nature09883
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