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Molecular Targets for Therapy

JAK inhibitors suppress t(8;21) fusion protein-induced leukemia

Leukemia volume 27, pages 2272–2279 (2013)Cite this article

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Abstract

Oncogenic mutations in components of the JAK/STAT pathway, including those in cytokine receptors and JAKs, lead to increased activity of downstream signaling and are frequently found in leukemia and other hematological disorders. Thus, small-molecule inhibitors of this pathway have been the focus of targeted therapy in these hematological diseases. We previously showed that t(8;21) fusion protein acute myeloid leukemia (AML)1–ETO and its alternatively spliced variant AML1–ETO9a (AE9a) enhance the JAK/STAT pathway via downregulation of CD45, a negative regulator of this pathway. To investigate the therapeutic potential of targeting JAK/STAT in t(8;21) leukemia, we examined the effects of a JAK2-selective inhibitor TG101209 and a JAK1/2-selective inhibitor INCB18424 on t(8;21) leukemia cells. TG101209 and INCB18424 inhibited proliferation and promoted apoptosis of these cells. Furthermore, TG101209 treatment in AE9a leukemia mice reduced tumor burden and significantly prolonged survival. TG101209 also significantly impaired the leukemia-initiating potential of AE9a leukemia cells in secondary recipient mice. These results demonstrate the potential therapeutic efficacy of JAK inhibitors in treating t(8;21) AML.

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References

  1. Vardiman JW, Harris NL, Brunning RD . The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002; 100: 2292–2302.

    Article  CAS  Google Scholar 

  2. Foran JM . New prognostic markers in acute myeloid leukemia: perspective from the clinic. Hematology Am Soc Hematol Educ Program 2010; 2010: 47–55.

    Article  Google Scholar 

  3. Lin TL, Smith BD . Prognostically important molecular markers in cytogenetically normal acute myeloid leukemia. Am J Med Sci 2011; 341: 404–408.

    Article  Google Scholar 

  4. Rowley JD . Identificaton of a translocation with quinacrine fluorescence in a patient with acute leukemia. Ann Genet 1973; 16: 109–112.

    CAS  PubMed  Google Scholar 

  5. Groupe Français de Cytogénétique Hématologique. Acute myelogenous leukemia with an 8;21 translocation. A report on 148 cases from the Groupe Francais de Cytogenetique Hematologique. Cancer Genet Cytogenet 1990; 44: 169–179.

    Article  Google Scholar 

  6. Peterson LF, Boyapati A, Ahn EY, Biggs JR, Okumura AJ, Lo MC et al. Acute myeloid leukemia with the 8q22;21q22 translocation: secondary mutational events and alternative t(8;21) transcripts. Blood 2007; 110: 799–805.

    Article  CAS  Google Scholar 

  7. Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR . AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 1996; 84: 321–330.

    Article  CAS  Google Scholar 

  8. Wang Q, Stacy T, Binder M, Marin-Padilla M, Sharpe AH, Speck NA . Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. PNAS 1996; 93: 3444–3449.

    Article  CAS  Google Scholar 

  9. Yergeau DA, Hetherington CJ, Wang Q, Zhang P, Sharpe AH, Binder M et al. Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nat Genet 1997; 15: 303–306.

    Article  CAS  Google Scholar 

  10. Okuda T, Cai Z, Yang S, Lenny N, Lyu CJ, van Deursen JM et al. Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors. Blood 1998; 91: 3134–3143.

    CAS  PubMed  Google Scholar 

  11. Peterson LF, Zhang DE . The 8;21 translocation in leukemogenesis. Oncogene 2004; 23: 4255–4262.

    Article  CAS  Google Scholar 

  12. Goyama S, Mulloy JC . Molecular pathogenesis of core binding factor leukemia: current knowledge and future prospects. Int J Hematol 2011; 94: 126–133.

    Article  CAS  Google Scholar 

  13. Yan M, Kanbe E, Peterson LF, Boyapati A, Miao Y, Wang Y et al. A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis. Nat Med 2006; 12: 945–949.

    Article  CAS  Google Scholar 

  14. Grimwade D, Walker H, Harrison G, Oliver F, Chatters S, Harrison CJ et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 2001; 98: 1312–1320.

    Article  CAS  Google Scholar 

  15. Burnett A, Wetzler M, Lowenberg B . Therapeutic advances in acute myeloid leukemia. J Clin Oncol 2011; 29: 487–494.

    Article  Google Scholar 

  16. Marcucci G, Mrozek K, Ruppert AS, Maharry K, Kolitz JE, Moore JO et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol 2005; 23: 5705–5717.

    Article  Google Scholar 

  17. Mrozek K, Bloomfield CD . Clinical significance of the most common chromosome translocations in adult acute myeloid leukemia. J Natl Cancer Inst Monogr 2008; 39: 52–57.

    Article  CAS  Google Scholar 

  18. Reikvam H, Hatfield KJ, Kittang AO, Hovland R, Bruserud O . Acute myeloid leukemia with the t(8;21) translocation: clinical consequences and biological implications. J Biomed Biotechnol 2011; 2011: 104631.

    Article  Google Scholar 

  19. Lo MC, Peterson LF, Yan M, Cong X, Jin F, Shia WJ et al. Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML. Blood 2012; 120: 1473–1484.

    Article  CAS  Google Scholar 

  20. Steelman LS, Abrams SL, Whelan J, Bertrand FE, Ludwig DE, Basecke J et al. Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia 2008; 22: 686–707.

    Article  CAS  Google Scholar 

  21. Levine RL, Pardanani A, Tefferi A, Gilliland DG . Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 2007; 7: 673–683.

    Article  CAS  Google Scholar 

  22. Jatiani SS, Baker SJ, Silverman LR, Reddy EP . JAK/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies. Genes Cancer 2010; 1: 979–993.

    Article  CAS  Google Scholar 

  23. Pardanani A, Hood J, Lasho T, Levine RL, Martin MB, Noronha G et al. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia 2007; 21: 1658–1668.

    Article  CAS  Google Scholar 

  24. Quintas-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood 2010; 115: 3109–3117.

    Article  CAS  Google Scholar 

  25. Yan M, Burel SA, Peterson LF, Kanbe E, Iwasaki H, Boyapati A et al. Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development. Proc Natl Acad Sci USA 2004; 101: 17186–17191.

    Article  CAS  Google Scholar 

  26. Peterson LF, Wang Y, Lo MC, Yan M, Kanbe E, Zhang DE . The multi-functional cellular adhesion molecule CD44 is regulated by the 8;21 chromosomal translocation. Leukemia 2007; 21: 2010–2019.

    Article  CAS  Google Scholar 

  27. Wernig G, Kharas MG, Okabe R, Moore SA, Leeman DS, Cullen DE et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell 2008; 13: 311–320.

    Article  CAS  Google Scholar 

  28. Geron I, Abrahamsson AE, Barroga CF, Kavalerchik E, Gotlib J, Hood JD et al. Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors. Cancer Cell 2008; 13: 321–330.

    Article  CAS  Google Scholar 

  29. Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A . TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia 2008; 22: 1790–1792.

    Article  CAS  Google Scholar 

  30. Reya T, Morrison SJ, Clarke MF, Weissman IL . Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105–111.

    Article  CAS  Google Scholar 

  31. Al-Hajj M, Clarke MF . Self-renewal and solid tumor stem cells. Oncogene 2004; 23: 7274–7282.

    Article  CAS  Google Scholar 

  32. Rosen JM, Jordan CT . The increasing complexity of the cancer stem cell paradigm. Science 2009; 324: 1670–1673.

    Article  CAS  Google Scholar 

  33. Wei J, Wunderlich M, Fox C, Alvarez S, Cigudosa JC, Wilhelm JS et al. Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell 2008; 13: 483–495.

    Article  CAS  Google Scholar 

  34. Lessard J, Faubert A, Sauvageau G . Genetic programs regulating HSC specification, maintenance and expansion. Oncogene 2004; 23: 7199–7209.

    Article  CAS  Google Scholar 

  35. Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science 2010; 327: 1650–1653.

    Article  CAS  Google Scholar 

  36. Lee JW, Kim YG, Soung YH, Han KJ, Kim SY, Rhim HS et al. The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene 2006; 25: 1434–1436.

    Article  CAS  Google Scholar 

  37. Steensma DP, McClure RF, Karp JE, Tefferi A, Lasho TL, Powell HL et al. JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. Leukemia 2006; 20: 971–978.

    Article  CAS  Google Scholar 

  38. Schnittger S, Bacher U, Kern W, Haferlach T, Haferlach C . JAK2V617F as progression marker in CMPD and as cooperative mutation in AML with trisomy 8 and t(8;21): a comparative study on 1103 CMPD and 269 AML cases. Leukemia 2007; 21: 1843–1845.

    Article  CAS  Google Scholar 

  39. Levine RL, Loriaux M, Huntly BJ, Loh ML, Beran M, Stoffregen E et al. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood 2005; 106: 3377–3379.

    Article  CAS  Google Scholar 

  40. Iwanaga E, Nanri T, Matsuno N, Kawakita T, Mitsuya H, Asou N . A JAK2-V617F activating mutation in addition to KIT and FLT3 mutations is associated with clinical outcome in patients with t(8;21)(q22;q22) acute myeloid leukemia. Haematologica 2009; 94: 433–435.

    Article  CAS  Google Scholar 

  41. Schnittger S, Bacher U, Kern W, Haferlach C, Haferlach T . JAK2 seems to be a typical cooperating mutation in therapy-related t(8;21)/ AML1-ETO-positive AML. Leukemia 2007; 21: 183–184.

    Article  CAS  Google Scholar 

  42. Illmer T, Schaich M, Ehninger G, Thiede C . Tyrosine kinase mutations of JAK2 are rare events in AML but influence prognosis of patients with CBF-leukemias. Haematologica 2007; 92: 137–138.

    Article  Google Scholar 

  43. Chou FS, Griesinger A, Wunderlich M, Lin S, Link KA, Shrestha M et al. The thrombopoietin/MPL/Bcl-xL pathway is essential for survival and self-renewal in human preleukemia induced by AML1-ETO. Blood 2012; 120: 709–719.

    Article  CAS  Google Scholar 

  44. Pulikkan JA, Madera D, Xue L, Bradley P, Landrette SF, Kuo YH et al. Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling. Blood 2012; 120: 868–879.

    Article  CAS  Google Scholar 

  45. Figueroa ME, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos PJ et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 2010; 17: 13–27.

    Article  CAS  Google Scholar 

  46. Watanabe D, Ezoe S, Fujimoto M, Kimura A, Saito Y, Nagai H et al. Suppressor of cytokine signalling-1 gene silencing in acute myeloid leukaemia and human haematopoietic cell lines. Br J Haematol 2004; 126: 726–735.

    Article  CAS  Google Scholar 

  47. Grisolano JL, O'Neal J, Cain J, Tomasson MH . An activated receptor tyrosine kinase, TEL/PDGFbetaR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice. Proc Natl Acad Sci USA 2003; 100: 9506–9511.

    Article  CAS  Google Scholar 

  48. Wang YY, Zhou GB, Yin T, Chen B, Shi JY, Liang WX et al. AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec. Proc Natl Acad Sci USA 2005; 102: 1104–1109.

    Article  CAS  Google Scholar 

  49. Wang YY, Zhao LJ, Wu CF, Liu P, Shi L, Liang Y et al. C-KIT mutation cooperates with full-length AML1-ETO to induce acute myeloid leukemia in mice. Proc Natl Acad Sci USA 2011; 108: 2450–2455.

    Article  CAS  Google Scholar 

  50. Liu S, Klisovic RB, Vukosavljevic T, Yu J, Paschka P, Huynh L et al. Targeting AML1/ETO-histone deacetylase repressor complex: a novel mechanism for valproic acid-mediated gene expression and cellular differentiation in AML1/ETO-positive acute myeloid leukemia cells. J Pharmacol Exp Ther 2007; 321: 953–960.

    Article  CAS  Google Scholar 

  51. Puccetti E, Beissert T, Guller S, Li JE, Hoelzer D, Ottmann OG et al. Leukemia-associated translocation products able to activate RAS modify PML and render cells sensitive to arsenic-induced apoptosis. Oncogene 2003; 22: 6900–6908.

    Article  CAS  Google Scholar 

  52. Zhou GB, Kang H, Wang L, Gao L, Liu P, Xie J et al. Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo. Blood 2007; 109: 3441–3450.

    Article  CAS  Google Scholar 

  53. Eghtedar A, Verstovsek S, Estrov Z, Burger J, Cortes J, Bivins C et al. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood 2012; 119: 4614–4618.

    Article  CAS  Google Scholar 

  54. Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 2010; 363: 1117–1127.

    Article  CAS  Google Scholar 

  55. Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol 2011; 29: 789–796.

    Article  CAS  Google Scholar 

  56. Traer E, MacKenzie R, Snead J, Agarwal A, Eiring AM, O'Hare T et al. Blockade of JAK2-mediated extrinsic survival signals restores sensitivity of CML cells to ABL inhibitors. Leukemia 2012; 26: 1140–1143.

    Article  CAS  Google Scholar 

  57. Nair RR, Tolentino JH, Argilagos RF, Zhang L, Pinilla-Ibarz J, Hazlehurst LA . Potentiation of Nilotinib-mediated cell death in the context of the bone marrow microenvironment requires a promiscuous JAK inhibitor in CML. Leuk Res 2012; 36: 756–763.

    Article  CAS  Google Scholar 

  58. Chen M, Gallipoli P, Degeer D, Sloma I, Forrest DL, Chan M et al. Targeting primitive chronic myeloid leukemia cells by effective inhibition of a new AHI-1-BCR-ABL-JAK2 complex. J Natl Cancer Inst 2013; 105: 405–423.

    Article  CAS  Google Scholar 

  59. Weisberg E, Liu Q, Nelson E, Kung AL, Christie AL, Bronson R et al. Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: synergism between FLT3 inhibitors, dasatinib/multi-targeted inhibitors and JAK inhibitors. Leukemia 2012; 26: 2233–2244.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank members of Zhang Lab and Dr Moshe Talpaz for valuable discussions, Jessica Mercer for editing the manuscript, Dr Nancy Zeleznik-Le for providing the MigR1-MLL-AF9-Flag construct and TargeGen/Sanofi for providing the JAK2 inhibitor TG101209. This work was supported by the National Institutes of Health R01CA104509 to D-EZ, and Leukemia and Lymphoma Society Fellowship 5122-07 to M-CL.

Author Contributions

M-CL and LFP designed and performed the experiments, analyzed the data and wrote the manuscript. MY, XC, JHH, RCD and DN performed some experiments. D-EZ supervised the research and manuscript preparation.

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Authors and Affiliations

  1. Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA

    M-C Lo, M Yan, X Cong, J H Hickman, R C DeKelver, D Niewerth & D-E Zhang

  2. Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    L F Peterson

  3. Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA

    J H Hickman, R C DeKelver & D-E Zhang

  4. Department of Pathology, University of California San Diego, La Jolla, CA, USA

    D-E Zhang

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  1. M-C Lo
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Lo, MC., Peterson, L., Yan, M. et al. JAK inhibitors suppress t(8;21) fusion protein-induced leukemia. Leukemia 27, 2272–2279 (2013). https://doi.org/10.1038/leu.2013.197

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