Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia


Tyrosine-kinase inhibitor (TKI) therapy for human cancers is not curative, and relapse occurs owing to the continued presence of tumor cells, referred to as minimal residual disease (MRD). The survival of MRD stem or progenitor cells in the absence of oncogenic kinase signaling, a phenomenon referred to as intrinsic resistance, depends on diverse growth factors. Here we report that oncogenic kinase and growth-factor signaling converge to induce the expression of the signaling proteins FBJ osteosarcoma oncogene (c-FOS, encoded by Fos) and dual-specificity phosphatase 1 (DUSP1). Genetic deletion of Fos and Dusp1 suppressed tumor growth in a BCR-ABL fusion protein kinase–induced mouse model of chronic myeloid leukemia (CML). Pharmacological inhibition of c-FOS, DUSP1 and BCR-ABL eradicated MRD in multiple in vivo models, as well as in mice xenotransplanted with patient-derived primary CML cells. Growth-factor signaling also conferred TKI resistance and induced FOS and DUSP1 expression in tumor cells modeling other types of kinase-driven leukemias. Our data demonstrate that c-FOS and DUSP1 expression levels determine the threshold of TKI efficacy, such that growth-factor-induced expression of c-FOS and DUSP1 confers intrinsic resistance to TKI therapy in a wide-ranging set of leukemias, and might represent a unifying Achilles' heel of kinase-driven cancers.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Expression of c-Fos, Dusp1, and Zfp36 constitutes a common signature of imatinib-resistant cells.
Figure 2: Genetic deletion of Fos and Dusp1 increases the response of BCR-ABL-induced leukemia to imatinib.
Figure 3: Chemical inhibition of c-Fos, Dusp1, and BCR-ABL eradicates minimal MRD in mice.
Figure 4: Inhibition of c-Fos, Dusp1, and BCR-ABL selectively eradicates CML cells.
Figure 5: Genetic or chemical inhibition of c-Fos and Dusp1 downregulates the Fos–Jun network while activating Jun–JunD target genes.
Figure 6: Inhibition of Dusp1 activates p38.

Accession codes

Primary accessions

Gene Expression Omnibus

Referenced accessions

Gene Expression Omnibus


  1. 1

    Daley, G.Q., Van Etten, R.A. & Baltimore, D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247, 824–830 (1990).

  2. 2

    Druker, B.J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat. Med. 2, 561–566 (1996).

  3. 3

    O'Hare, T., Zabriskie, M.S., Eiring, A.M. & Deininger, M.W. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat. Rev. Cancer 12, 513–526 (2012).

  4. 4

    Rousselot, P. et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 109, 58–60 (2007).

  5. 5

    Mahon, F.X. et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 11, 1029–1035 (2010).

  6. 6

    Ross, D.M. et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 122, 515–522 (2013).

  7. 7

    Chu, S. et al. Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood 105, 2093–2098 (2005).

  8. 8

    Savona, M. & Talpaz, M. Getting to the stem of chronic myeloid leukaemia. Nat. Rev. Cancer 8, 341–350 (2008).

  9. 9

    Azam, M., Latek, R.R. & Daley, G.Q. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 112, 831–843 (2003).

  10. 10

    Krause, D.S. & Van Etten, R.A. Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med. 353, 172–187 (2005).

  11. 11

    Weinstein, I.B. Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science 297, 63–64 (2002).

  12. 12

    Sawyers, C.L. Shifting paradigms: the seeds of oncogene addiction. Nat. Med. 15, 1158–1161 (2009).

  13. 13

    Pagliarini, R., Shao, W. & Sellers, W.R. Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure. EMBO Rep. 16, 280–296 (2015).

  14. 14

    Reddy, A. & Kaelin, W.G., Jr. Using cancer genetics to guide the selection of anticancer drug targets. Curr. Opin. Pharmacol. 2, 366–373 (2002).

  15. 15

    Kaelin, W.G., Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5, 689–698 (2005).

  16. 16

    Kamb, A. Consequences of nonadaptive alterations in cancer. Mol. Biol. Cell 14, 2201–2205 (2003).

  17. 17

    Mills, G.B., Lu, Y. & Kohn, E.C. Linking molecular therapeutics to molecular diagnostics: inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo. Proc. Natl. Acad. Sci. USA 98, 10031–10033 (2001).

  18. 18

    Sharma, S.V. & Settleman, J. Exploiting the balance between life and death: targeted cancer therapy and “oncogenic shock”. Biochem. Pharmacol. 80, 666–673 (2010).

  19. 19

    Sharma, S.V. & Settleman, J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev. 21, 3214–3231 (2007).

  20. 20

    Corbin, A.S. et al. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J. Clin. Invest. 121, 396–409 (2011).

  21. 21

    Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).

  22. 22

    Wilson, T.R. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487, 505–509 (2012).

  23. 23

    Bruennert, D. et al. Early in vivo changes of the transcriptome in Philadelphia chromosome-positive CD34+ cells from patients with chronic myelogenous leukaemia following imatinib therapy. Leukemia 23, 983–985 (2009).

  24. 24

    Eferl, R. & Wagner, E.F. AP-1: a double-edged sword in tumorigenesis. Nat. Rev. Cancer 3, 859–868 (2003).

  25. 25

    Lawan, A., Shi, H., Gatzke, F. & Bennett, A.M. Diversity and specificity of the mitogen-activated protein kinase phosphatase-1 functions. Cell. Mol. Life Sci. 70, 223–237 (2013).

  26. 26

    Jeffrey, K.L., Camps, M., Rommel, C. & Mackay, C.R. Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses. Nat. Rev. Drug Discov. 6, 391–403 (2007).

  27. 27

    Brooks, S.A. & Blackshear, P.J. Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action. Biochim. Biophys. Acta 1829, 666–679 (2013).

  28. 28

    Dorfman, K. et al. Disruption of the erp/mkp-1 gene does not affect mouse development: normal MAP kinase activity in ERP/MKP-1-deficient fibroblasts. Oncogene 13, 925–931 (1996).

  29. 29

    Zhang, J. et al. c-fos regulates neuronal excitability and survival. Nat. Genet. 30, 416–420 (2002).

  30. 30

    Zhao, C. et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458, 776–779 (2009).

  31. 31

    Ransone, L.J., Visvader, J., Wamsley, P. & Verma, I.M. Trans-dominant negative mutants of Fos and Jun. Proc. Natl. Acad. Sci. USA 87, 3806–3810 (1990).

  32. 32

    Molina, G. et al. Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages. Nat. Chem. Biol. 5, 680–687 (2009).

  33. 33

    Huang, T.S., Lee, S.C. & Lin, J.K. Suppression of c-Jun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells. Proc. Natl. Acad. Sci. USA 88, 5292–5296 (1991).

  34. 34

    Park, S., Lee, D.K. & Yang, C.H. Inhibition of fos-jun-DNA complex formation by dihydroguaiaretic acid and in vitro cytotoxic effects on cancer cells. Cancer Lett. 127, 23–28 (1998).

  35. 35

    Padhye, S. et al. Fluorocurcumins as cyclooxygenase-2 inhibitor: molecular docking, pharmacokinetics and tissue distribution in mice. Pharm. Res. 26, 2438–2445 (2009).

  36. 36

    Koschmieder, S. et al. Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis. Blood 105, 324–334 (2005).

  37. 37

    Li, L. et al. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 21, 266–281 (2012).

  38. 38

    Copland, M. et al. BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors. Blood 111, 2843–2853 (2008).

  39. 39

    Angel, P. & Karin, M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim. Biophys. Acta 1072, 129–157 (1991).

  40. 40

    Owens, D.M. & Keyse, S.M. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 26, 3203–3213 (2007).

  41. 41

    Boutros, T., Chevet, E. & Metrakos, P. Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol. Rev. 60, 261–310 (2008).

  42. 42

    Groom, L.A., Sneddon, A.A., Alessi, D.R., Dowd, S. & Keyse, S.M. Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual-specificity phosphatase. EMBO J. 15, 3621–3632 (1996).

  43. 43

    Fjeld, C.C., Rice, A.E., Kim, Y., Gee, K.R. & Denu, J.M. Mechanistic basis for catalytic activation of mitogen-activated protein kinase phosphatase 3 by extracellular signal-regulated kinase. J. Biol. Chem. 275, 6749–6757 (2000).

  44. 44

    Zhao, Q. et al. MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock. J. Exp. Med. 203, 131–140 (2006).

  45. 45

    Hirsch, D.D. & Stork, P.J. Mitogen-activated protein kinase phosphatases inactivate stress-activated protein kinase pathways in vivo. J. Biol. Chem. 272, 4568–4575 (1997).

  46. 46

    Young, P.R. et al. Pyridinyl imidazole inhibitors of p38 mitogen-activated protein kinase bind in the ATP site. J. Biol. Chem. 272, 12116–12121 (1997).

  47. 47

    Bennett, B.L. et al. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl. Acad. Sci. USA 98, 13681–13686 (2001).

  48. 48

    Shojaee, S. et al. Erk negative feedback control enables pre-B cell transformation and represents a therapeutic target in acute lymphoblastic leukemia. Cancer Cell 28, 114–128 (2015).

  49. 49

    Hrustanovic, G. et al. RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nat. Med. 21, 1038–1047 (2015).

  50. 50

    Zhang, B. et al. Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell 21, 577–592 (2012).

  51. 51

    Reynaud, D. et al. IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development. Cancer Cell 20, 661–673 (2011).

  52. 52

    Welner, R.S. et al. Treatment of chronic myelogenous leukemia by blocking cytokine alterations found in normal stem and progenitor cells. Cancer Cell 27, 671–681 (2015).

  53. 53

    Roberts, K.G. et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 22, 153–166 (2012).

  54. 54

    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).

  55. 55

    Chang, K.H. et al. Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival. Blood 120, 800–811 (2012).

  56. 56

    Bagger, F.O. et al. BloodSpot: a database of gene expression profiles and transcriptional programs for healthy and malignant haematopoiesis. Nucleic Acids Res. 44 D1, D917–D924 (2016).

  57. 57

    Jørgensen, H.G., Allan, E.K., Jordanides, N.E., Mountford, J.C. & Holyoake, T.L. Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood 109, 4016–4019 (2007).

  58. 58

    Holyoake, T.L. & Vetrie, D. The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood (2017).

  59. 59

    Kesarwani, M. et al. Targeting substrate-site in Jak2 kinase prevents emergence of genetic resistance. Sci. Rep. 5, 14538 (2015).

  60. 60

    Azam, M., Seeliger, M.A., Gray, N.S., Kuriyan, J. & Daley, G.Q. Activation of tyrosine kinases by mutation of the gatekeeper threonine. Nat. Struct. Mol. Biol. 15, 1109–1118 (2008).

  61. 61

    Komurov, K., Dursun, S., Erdin, S. & Ram, P.T. NetWalker: a contextual network analysis tool for functional genomics. BMC Genomics 13, 282 (2012).

Download references


The authors are thankful to H. Singh and Y. Zheng for providing critical feedback on this study. We are thankful to G. Daley for providing the BaF3-BA cells and T. Reya for the MSCV-BCR-ABL-Ires-YFP constructs. We are thankful to M. Carroll for providing the patient samples from the CML blast crisis. This study was supported by grants to M.A. from the NCI (1RO1CA155091), Leukemia Research Foundation and V Foundation and from the NHLBI (R21HL114074-01).

Author information

Experiments were conceived and designed by M.K. and M.A. Experiments were performed by M.K., Z.K., A.G., E.H., S.R, Z.S., M.F.B., T.L., M.X., J.C.M., J.A.C., and H.L.G. Bioinformatics analysis of microarrays and RNA-seq data were performed by M.K. and K.K. The manuscript was written by M.K. and M.A.

Correspondence to Mohammad Azam.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures and Legends

Supplementary Figures 1–15 (PDF 8989 kb)

Supplementary Methods

Supplementary Methods (PDF 258 kb)

Supplementary Tables

Supplementary Tables 1–5 (PDF 453 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading