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Acute myeloid leukemia

FGFR1 fusion kinase regulation of MYC expression drives development of stem cell leukemia/lymphoma syndrome

Leukemiavolume 32pages23632373 (2018) | Download Citation

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Abstract

Oncogenic transformation of hematopoietic stem cells by chimeric fusion kinases causing constitutive activation of FGFR1 leads to a stem cell leukemia/lymphoma (SCLL) syndrome, accompanied by widespread dysregulation of gene activity. We now show that FGFR1 activation is associated with upregulation of MYC and pharmacological suppression of FGFR1 activation leads to downregulation of MYC and suppression of MYC target genes. Luciferase reporter assays demonstrate that FGFR1 can directly regulate MYC expression and this effect is enhanced in the presence of chimeric FGFR1 kinases. In SCLL cells, a truncated form of FGFR1 is generated by granzyme B cleavage of the chimeric kinases, producing a nucleus-restricted derivative that can bind MYC regulatory regions. Mutation of the granzyme B cleavage site prevents relocation to the nucleus but does not suppress MYC activation, suggesting additional mechanisms of MYC activation in the presence of cytoplasm-restricted chimeric kinases. We show that one of these mechanisms involves activating cytoplasmic STAT5, which upregulates MYC independent of the truncated FGFR1 kinase. Targeting MYC function using shRNA knockdown and 10054-F8 in SCLL cells leads to inhibition of cell proliferation and synergizes with the BGJ398 FGFR1 inhibitor, suggesting a combination therapy that could be used in the treatment of SCLL.

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References

  1. 1.

    Jackson CC, Medeiros LJ, Miranda RN. 8p11 myeloproliferative syndrome: a review. Hum Pathol. 2010;41:461–76.

  2. 2.

    Roumiantsev S, Krause DS, Neumann CA, Dimitri CA, Asiedu F, Cross NC, et al. Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198-FGFR1 and BCR-FGFR1 fusion genes from 8p11 translocations. Cancer Cell. 2004;5:287–98.

  3. 3.

    Ren M, Li X, Cowell JK. Genetic fingerprinting of the development and progression of T-cell lymphoma in a murine model of atypical myeloproliferative disorder initiated by the ZNF198-fibroblast growth factor receptor-1 chimeric tyrosine kinase. Blood. 2009;114:1576–84.

  4. 4.

    Ren M, Qin H, Kitamura E, Cowell JK. Dysregulated signaling pathways in the development of CNTRL-FGFR1-induced myeloid and lymphoid malignancies associated with FGFR1 in human and mouse models. Blood. 2013;122:1007–16.

  5. 5.

    Qin H, Wu Q, Cowell JK, Ren M. FGFR1OP2-FGFR1 induced myeloid leukemia and T-cell lymphoma in a mouse model. Haematologica. 2016;101:e91–94.

  6. 6.

    Ren M, Cowell JK. Constitutive Notch pathway activation in murine ZMYM2-FGFR1-induced T-cell lymphomas associated with atypical myeloproliferative disease. Blood. 2011;117:6837–47.

  7. 7.

    Ren M, Qin H, Wu Q, Savage NM, George TI, Cowell JK. Development of ZMYM2-FGFR1 driven AML in human CD34+cells in immunocompromised mice. Int J Cancer. 2016;139:836–40.

  8. 8.

    Cowell JK, Qin H, Chang CS, Kitamura E, Ren M. A model of BCR-FGFR1 driven human AML in immunocompromised mice. Br J Haematol. 2016;175:542–5.

  9. 9.

    Kress TR, Sabo A, Amati B. MYC: connecting selective transcriptional control to global RNA production. Nat Rev Cancer. 2015;15:593–607.

  10. 10.

    Delgado MD, Leon J. Myc roles in hematopoiesis and leukemia. Genes Cancer. 2010;1:605–16.

  11. 11.

    Wang C, Lisanti MP, Liao DJ. Reviewing once more the c-myc and Ras collaboration: converging at the cyclin D1-CDK4 complex and challenging basic concepts of cancer biology. Cell Cycle. 2011;10:57–67.

  12. 12.

    Hu T, Chong Y, Qin H, Kitamura E, Chang CS, Silva J, et al. The miR-17/92 cluster is involved in the molecular etiology of the SCLL syndrome driven by the BCR-FGFR1 chimeric kinase. Oncogene. 2017. https://doi.org/10.1038/s41388-017-0091-1.

  13. 13.

    Hu T, Pi W, Zhu X, Yu M, Ha H, Shi H, et al. Long non-coding RNAs transcribed by ERV-9 LTR retrotransposon act in cis to modulate long-range LTR enhancer function. Nucleic Acids Res. 2017;45:4479–92.

  14. 14.

    Ghoshal P, Teng Y, Lesoon LA, Cowell JK. HIF1A induces expression of the WASF3 metastasis-associated gene under hypoxic conditions. Int J Cancer. 2012;131:E905–915.

  15. 15.

    Facchini LM, Chen S, Marhin WW, Lear JN, Penn LZ. The Myc negative autoregulation mechanism requires Myc-Max association and involves the c-myc P2 minimal promoter. Mol Cell Biol. 1997;17:100–14.

  16. 16.

    Silva J, Chang CS, Hu T, Qin H, Kitamura E, Hawthorn L, et al. Gene expression profiling during progression of FGFR1 driven AML in a mouse model of Stem Cell Leukemia Lymphoma syndrome. BMC Cancer. 2017

  17. 17.

    Ren M, Tidwell JA, Sharma S, Cowell JK. Acute progression of BCR-FGFR1 induced murine B-lympho/myeloproliferative disorder suggests involvement of lineages at the pro-B cell stage. PLoS ONE. 2012;7:e38265.

  18. 18.

    Loeb CR, Harris JL, Craik CS. Granzyme B proteolyzes receptors important to proliferation and survival, tipping the balance toward apoptosis. J Biol Chem. 2006;281:28326–35.

  19. 19.

    Chioni AM, Grose R. FGFR1 cleavage and nuclear translocation regulates breast cancer cell behavior. J Cell Biol. 2012;197:801–17.

  20. 20.

    Landt SG, Marinov GK, Kundaje A, Kheradpour P, Pauli F, Batzoglou S, et al. ChIP-seq guidelines and practices of the ENCODE and modENCODE consortia. Genome Res. 2012;22:1813–31.

  21. 21.

    Wu Q, Bhole A, Qin H, Karp J, Malek S, Cowell JK, et al. SCLL targeting FGFR1 to suppress leukemogenesis in syndromic and de novo AML in murine models. Oncotarget. 2016;7:10.

  22. 22.

    Baumann H, Kunapuli P, Tracy E, Cowell JK. The oncogenic fusion protein-tyrosine kinase ZNF198/fibroblast growth factor receptor-1 has signaling function comparable with interleukin-6 cytokine receptors. J Biol Chem. 2003;278:16198–208.

  23. 23.

    Alvarez JV, Frank DA. Genome-wide analysis of STAT target genes: elucidating the mechanism of STAT-mediated oncogenesis. Cancer Biol Ther. 2004;3:1045–50.

  24. 24.

    Bild AH, Yao G, Chang JT, Wang Q, Potti A, Chasse D, et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature. 2006;439:353–7.

  25. 25.

    Yin X, Giap C, Lazo JS, Prochownik EV. Low molecular weight inhibitors of Myc-Max interaction and function. Oncogene. 2003;22:6151–9.

  26. 26.

    Pinz S, Unser S, Rascle A. Signal transducer and activator of transcription STAT5 is recruited to c-Myc super-enhancer. BMC Mol Biol. 2016;17:10.

  27. 27.

    Ren M, Qin H, Ren R, Tidwell J, Cowell JK. Src activation plays an important key role in lymphomagenesis induced by FGFR1 fusion kinases. Cancer Res. 2011;71:7312–22.

  28. 28.

    Ren M, Qin H, Ren R, Cowell JK. Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities. Leukemia. 2013;27:32–40.

  29. 29.

    Heath C, Cross NC. Critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1. J Biol Chem. 2004;279:6666–73.

  30. 30.

    Smedley D, Demiroglu A, Abdul-Rauf M, Heath C, Cooper C, Shipley J, et al. ZNF198-FGFR1 transforms Ba/F3 cells to growth factor independence and results in high level tyrosine phosphorylation of STATS 1 and 5. Neoplasia. 1999;1:349–55.

  31. 31.

    Gu TL, Goss VL, Reeves C, Popova L, Nardone J, Macneill J, et al. Phosphotyrosine profiling identifies the KG-1 cell line as a model for the study of FGFR1 fusions in acute myeloid leukemia. Blood. 2006;108:4202–4.

  32. 32.

    Guasch G, Ollendorff V, Borg JP, Birnbaum D, Pebusque MJ. 8p12 stem cell myeloproliferative disorder: the FOP-fibroblast growth factor receptor 1 fusion protein of the t(6;8) translocation induces cell survival mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt/mTOR pathways. Mol Cell Biol. 2001;21:8129–42.

  33. 33.

    Bowman T, Broome MA, Sinibaldi D, Wharton W, Pledger WJ, Sedivy JM, et al. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc Natl Acad Sci USA. 2001;98:7319–24.

  34. 34.

    Luo H, Li Q, O’Neal J, Kreisel F, Le Beau MM, Tomasson MH. c-Myc rapidly induces acute myeloid leukemia in mice without evidence of lymphoma-associated antiapoptotic mutations. Blood. 2005;106:2452–61.

  35. 35.

    Cowell JK, Qin H, Hu T, Wu Q, Bhole A, Ren M. Mutation in the FGFR1 tyrosine kinase domain or inactivation of PTEN is associated with acquired resistance to FGFR inhibitors in FGFR1-driven leukemia/lymphomas. Int J Cancer. 2017;141:1822–9.

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Acknowledgements

This work was supported by grant CA076167 from the National Institutes of Health.

Author information

Affiliations

  1. Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA

    • Tianxiang Hu
    • , Qing Wu
    • , Yating Chong
    • , Haiyan Qin
    •  & John K. Cowell
  2. Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA

    • Candace J. Poole
    •  & Jan van Riggelen
  3. Consortium for Health and Military Performance (CHAMP), Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA

    • Mingqiang Ren

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Mingqiang Ren or John K. Cowell.

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DOI

https://doi.org/10.1038/s41375-018-0124-y