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

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.

Accession codes

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.

References

  1. 1

    Druker, B. J. et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N. Engl. J. Med. 344, 1038–1042 (2001)

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Armstrong, S. A. et al. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell 3, 173–183 (2003)

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Meydan, N. et al. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379, 645–648 (1996)

    ADS  CAS  PubMed  Article  Google Scholar 

  4. 4

    Shah, N. P. et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305, 399–401 (2004)

    ADS  CAS  Article  PubMed  Google Scholar 

  5. 5

    O’Hare, T. et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16, 401–412 (2009)

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6

    Graham, S. M. et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro . Blood 99, 319–325 (2002)

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Naka, K. et al. TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463, 676–680 (2010)

    ADS  CAS  PubMed  Article  Google Scholar 

  8. 8

    Oravecz-Wilson, K. I. et al. Persistence of leukemia-initiating cells in a conditional knockin model of an imatinib-responsive myeloproliferative disorder. Cancer Cell 16, 137–148 (2009)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9

    Saito, M. et al. A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell 12, 280–292 (2007)

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Pratilas, C. A. et al. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc. Natl Acad. Sci. USA 106, 4519–4524 (2009)

    ADS  CAS  PubMed  Article  Google Scholar 

  11. 11

    Choudhary, C. et al. Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. Mol. Cell 36, 326–339 (2009)

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Janes, M. R. et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nature Med. 16, 205–213 (2010)

    ADS  CAS  PubMed  Article  Google Scholar 

  13. 13

    Walker, S. R., Nelson, E. A. & Frank, D. A. STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas. Oncogene 26, 224–233 (2007)

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Duy, C. et al. BCL6 is critical for the development of a diverse primary B cell repertoire. J. Exp. Med. 207, 1209–1221 (2010)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15

    Fernandez de Mattos, S. et al. FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism. Mol. Cell. Biol. 24, 10058–10071 (2004)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16

    Phan, R. T. & Dalla-Favera, R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 432, 635–639 (2004)

    ADS  CAS  PubMed  Article  Google Scholar 

  17. 17

    Wendel, H. G. et al. Loss of p53 impedes the antileukemic response to BCR-ABL inhibition. Proc. Natl Acad. Sci. USA 103, 7444–7449 (2006)

    ADS  CAS  PubMed  Article  Google Scholar 

  18. 18

    Goldberg, Z., Levav, Y., Krichevsky, S., Fibach, E. & Haupt, Y. Treatment of chronic myeloid leukemia cells with imatinib (STI571) impairs p53 accumulation in response to DNA damage. Cell Cycle 3, 1188–1195 (2004)

    CAS  PubMed  Article  Google Scholar 

  19. 19

    Skorta, I. et al. Imatinib mesylate induces cisplatin hypersensitivity in Bcr-Abl+ cells by differential modulation of p53 transcriptional and proapoptotic activity. Cancer Res. 69, 9337–9345 (2009)

    CAS  PubMed  Article  Google Scholar 

  20. 20

    Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649–659 (1997)

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005)

    ADS  CAS  PubMed  Article  Google Scholar 

  22. 22

    Mullighan, C. G. et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 322, 1377–1380 (2008)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Williams, R. T., Roussel, M. F. & Sherr, C. J. Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia. Proc. Natl Acad. Sci. USA 103, 6688–6693 (2006)

    ADS  CAS  PubMed  Article  Google Scholar 

  24. 24

    Krause, D. S., Lazarides, K., von Andrian, U. H. & Van Etten, R. A. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nature Med. 12, 1175–1180 (2006)

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Cerchietti, L. C. et al. A peptomimetic inhibitor of BCL6 with potent antilymphoma effects in vitro and in vivo . Blood 113, 3397–3405 (2009)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26

    Shaffer, A. L. et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13, 199–212 (2000)

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Williams, R. T. den, B. W. & Sherr, C. J. Cytokine-dependent imatinib resistance in mouse BCR-ABL+, Arf-null lymphoblastic leukemia. Genes Dev. 21, 2283–2287 (2007)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28

    Gruber, T. A., Chang, M. S., Sposto, R. & Muschen, M. Activation-induced cytidine deaminase accelerates clonal evolution in BCR-ABL1-driven B-cell lineage acute lymphoblastic leukemia. Cancer Res. 70, 7411–7420 (2010)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29

    Cerchietti, L. C. et al. A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo . Cancer Cell 17, 400–411 (2010)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Pear, W. S. et al. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood 92, 3780–3792 (1998)

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Onishi, M. et al. Identification and characterization of a constitutively active STAT5 mutant that promotes cell proliferation. Mol. Cell. Biol. 18, 3871–3879 (1998)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

    Godar, S. et al. Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression. Cell 134, 62–73 (2008)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33

    Kumar, M. S. et al. Dicer1 functions as a haploinsufficient tumor suppressor. Genes Dev. 23, 2700–2704 (2009)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    Soneoka, Y. et al. A transient three-plasmid expression system for the production of high titer retroviral vectors. Nucleic Acids Res. 23, 628–633 (1995)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35

    Dent, A. L., Shaffer, A. L., Yu, X., Allman, D. & Staudt, L. M. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276, 589–592 (1997)

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Ye, B. H. et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nature Genet. 16, 161–170 (1997)

    CAS  PubMed  Article  Google Scholar 

  37. 37

    Cui, Y. et al. Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol. Cell. Biol. 24, 8037–8047 (2004)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38

    Groszer, M. et al. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294, 2186–2189 (2001)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Ahmad, K. F. et al. Mechanism of SMRT corepressor recruitment by the BCL6 BTB domain. Mol. Cell 12, 1551–1564 (2003)

    CAS  PubMed  Article  Google Scholar 

  40. 40

    Ghetu, A. F. et al. Structure of a BCOR corepressor peptide in complex with the BCL6 BTB domain dimer. Mol. Cell 29, 384–391 (2008)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

    Polo, J. M. et al. Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells. Nature Med. 10, 1329–1335 (2004)

    CAS  PubMed  Article  Google Scholar 

  42. 42

    Chakravarti, L. &. Roy, (1967). Handbook of Methods of Applied Statistics, Volume I, John Wiley and Sons, pp. 392-394. (1967)

  43. 43

    Ci, W. et al. The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL. Blood 113, 5536–5548 (2009)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44

    Polo, J. M. et al. Transcriptional signature with differential expression of BCL6 target genes accurately identifies BCL6-dependent diffuse large B cell lymphomas. Proc. Natl Acad. Sci. USA 104, 3207–3212 (2007)

    ADS  CAS  PubMed  Article  Google Scholar 

  45. 45

    Trageser, D. et al. Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function. J. Exp. Med. 206, 1739–1753 (2009)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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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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Correspondence to Markus Müschen.

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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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