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BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR–ABL1 kinase inhibition

Nature volume 473, pages 384–388 (2011)Cite this article

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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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Figure 1: Regulation of BCL6 expression in BCR–ABL1 ALL cells.
Figure 2: BCL6 is required for transcriptional inactivation of the Arf/p53 pathway in BCR–ABL1 ALL.
Figure 3: BCL6 is required for leukaemia initiation in BCR–ABL1 ALL.
Figure 4: BCL6 promotes survival of TKI-treated BCR–ABL1 ALL cells.

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Primary accessions

Gene Expression Omnibus

Data deposits

The gene expression and ChIP data are deposited in NCBI’s Gene Expression Omnibus under accession numbers GSE23743, GSE24426, GSE15179, GSE11794, GSE10086, GSE20987 and GSE24400.

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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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Authors and Affiliations

  1. Department of Laboratory Medicine, University of California San Francisco, San Francisco, 94143, California, USA

    Cihangir Duy, Christian Hurtz, Seyedmehdi Shojaee, Srividya Swaminathan, Lars Klemm, Rahul Nahar & Markus Müschen

  2. Department of Pediatrics, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, 90027, California, USA

    Cihangir Duy, Soo-mi Kweon, Rahul Nahar, Eugene Park, Yong-mi Kim, Nora Heisterkamp & Markus Müschen

  3. Departments of Medicine and Pharmacology, Weill Cornell Medical College, New York, 10065, New York, USA

    Leandro Cerchietti, Huimin Geng & Ari Melnick

  4. Department of Hematology and Oncology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

    Melanie Braig

  5. Department of Hematology and Oncology, Universität Heidelberg, Klinikum Mannheim, Mannheim, Germany,

    Wolf-Karsten Hofmann

  6. Faculty of Biology, BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-Universität Freiburg and Max-Planck-Institute for Immunobiology, Freiburg, Germany ,

    Christian Hurtz, Sebastian Herzog & Hassan Jumaa

  7. Division of Hematology and Oncology, Cedars Sinai Medical Center, Los Angeles, 90095, California, USA

    H. Phillip Koeffler

  8. Department of Cell Biology, Albert Einstein College of Medicine, Bronx, 10461, New York, USA

    J. Jessica Yu & B. Hilda Ye

  9. Department of Molecular Pharmacology, University of California Los Angeles, Los Angeles, 90095, California, USA

    Thomas G. Graeber & Hong Wu

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  1. Cihangir Duy
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Contributions

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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Correspondence to Markus Müschen.

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The authors declare no competing financial interests.

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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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