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  • Original Article
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Chronic Myeloproliferative Neoplasias

The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity

Leukemia volume 26, pages 481–489 (2012)Cite this article

Abstract

Myeloproliferative neoplasms are characterized by overproduction of myeloid lineage cells with frequent acquisition of oncogenic JAK2V617F kinase mutations. The molecular mechanisms that regulate energy requirements in these diseases are poorly understood. Transformed cells tend to rely on fermentation instead of more efficient oxidative phosphorylation for energy production. Our data in JAK2V617F-transformed cells show that growth and metabolic activity were strictly dependent on the presence of glucose. Uptake of glucose and cell surface expression of the glucose transporter Glut1 required the oncogenic tyrosine kinase. Importantly, JAK2V617F as well as active STAT5 increased the expression of the inducible rate-limiting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), which controls glycolytic flux through 6-phosphofructo-1-kinase. PFKFB3 was required for JAK2V617F-dependent lactate production, oxidative metabolic activity and glucose uptake. Targeted knockdown of PFKFB3 also limited cell growth under normoxic and hypoxic conditions and blocked in vivo tumor formation in mice. Overall, these data suggest that inducible PFKFB3 is required for increased growth, metabolic activity and is regulated through active JAK2 and STAT5. Novel therapies that specifically block PFKFB3 activity or expression would, therefore, be expected to inhibit JAK2/STAT5-dependent malignancies and related cancers.

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References

  1. Levine RL, Gilliland DG . Myeloproliferative disorders. Blood 2008; 112: 2190–2198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bercovich D, Ganmore I, Scott LM, Wainreb G, Birger Y, Elimelech A et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet 2008; 372: 1484–1492.

    Article  CAS  PubMed  Google Scholar 

  3. Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B et al. The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2. Cancer Res 2005; 65: 2662–2667.

    Article  CAS  PubMed  Google Scholar 

  4. Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D et al. Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 1998; 93: 841–850.

    Article  CAS  PubMed  Google Scholar 

  5. Hennighausen L, Robinson GW . Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. Genes Dev 2008; 22: 711–721.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Warburg O . On respiratory impairment in cancer cells. Science 1956; 124: 269–270.

    CAS  PubMed  Google Scholar 

  7. Pedersen PL . Tumor mitochondria and the bioenergetics of cancer cells. Prog Exp Tumor Res 1978; 22: 190–274.

    Article  CAS  PubMed  Google Scholar 

  8. Yalcin A, Telang S, Clem B, Chesney J . Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases in cancer. Exp Mol Pathol 2009; 86: 174–179.

    Article  CAS  PubMed  Google Scholar 

  9. Van Schaftingen E, Hue L, Hers HG . Fructose 2,6-bisphosphate, the probably structure of the glucose- and glucagon-sensitive stimulator of phosphofructokinase. Biochem J 1980; 192: 897–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Uyeda K, Furuya E, Luby LJ . The effect of natural and synthetic D-fructose 2,6-bisphosphate on the regulatory kinetic properties of liver and muscle phosphofructokinases. J Biol Chem 1981; 256: 8394–8399.

    CAS  PubMed  Google Scholar 

  11. Van Schaftingen E, Hers HG . Inhibition of fructose-1,6-bisphosphatase by fructose 2,6-biphosphate. Proc Natl Acad Sci USA 1981; 78: 2861–2863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wernig G, Gonneville JR, Crowley BJ, Rodrigues MS, Reddy MM, Hudon HE et al. The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes. Blood 2008; 111: 3751–3759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Reddy MM, Fernandes MS, Salgia R, Levine RL, Griffin JD, Sattler M . NADPH oxidases regulate cell growth and migration in myeloid cells transformed by oncogenic tyrosine kinases. Leukemia 2011; 25: 281–289.

    Article  CAS  PubMed  Google Scholar 

  14. Fernandes MS, Reddy MM, Gonneville JR, DeRoo SC, Podar K, Griffin JD et al. BCR-ABL promotes the frequency of mutagenic single-strand annealing DNA repair. Blood 2009; 114: 1813–1819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Van Schaftingen E, Lederer B, Bartrons R, Hers HG . A kinetic study of pyrophosphate: fructose-6-phosphate phosphotransferase from potato tubers. Application to a microassay of fructose 2,6-bisphosphate. Eur J Biochem 1982; 129: 191–195.

    Article  CAS  PubMed  Google Scholar 

  16. Gordan JD, Thompson CB, Simon MC . HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 2007; 12: 108–113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dang CV, Kim JW, Gao P, Yustein J . The interplay between MYC and HIF in cancer. Nat Rev Cancer 2008; 8: 51–56.

    Article  CAS  PubMed  Google Scholar 

  18. Clem B, Telang S, Clem A, Yalcin A, Meier J, Simmons A et al. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol Cancer Ther 2008; 7: 110–120.

    Article  CAS  PubMed  Google Scholar 

  19. Fatrai S, Wierenga AT, Daenen SM, Vellenga E, Schuringa JJ . Identification of HIF2alpha as an important STAT5 target gene in human hematopoietic stem cells. Blood 2011; 117: 3320–3330.

    Article  CAS  PubMed  Google Scholar 

  20. Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP . The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol 2009; 11: 747–752.

    Article  CAS  PubMed  Google Scholar 

  21. Bando H, Atsumi T, Nishio T, Niwa H, Mishima S, Shimizu C et al. Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer. Clin Cancer Res 2005; 11: 5784–5792.

    Article  CAS  PubMed  Google Scholar 

  22. Kessler R, Eschrich K . Splice isoforms of ubiquitous 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in human brain. Brain Res Mol Brain Res 2001; 87: 190–195.

    Article  CAS  PubMed  Google Scholar 

  23. Ahonen TJ, Xie J, LeBaron MJ, Zhu J, Nurmi M, Alanen K et al. Inhibition of transcription factor Stat5 induces cell death of human prostate cancer cells. J Biol Chem 2003; 278: 27287–27292.

    Article  CAS  PubMed  Google Scholar 

  24. Lai SY, Johnson FM . Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: implications for future therapeutic approaches. Drug Resist Updat 2010; 13: 67–78.

    Article  CAS  PubMed  Google Scholar 

  25. Clevenger CV . Roles and regulation of stat family transcription factors in human breast cancer. Am J Pathol 2004; 165: 1449–1460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Atsumi T, Chesney J, Metz C, Leng L, Donnelly S, Makita Z et al. High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res 2002; 62: 5881–5887.

    CAS  PubMed  Google Scholar 

  27. Kessler R, Bleichert F, Warnke JP, Eschrich K . 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) is up-regulated in high-grade astrocytomas. J Neurooncol 2008; 86: 257–264.

    Article  CAS  PubMed  Google Scholar 

  28. Fang M, Shen Z, Huang S, Zhao L, Chen S, Mak TW et al. The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell 2010; 143: 711–724.

    Article  CAS  PubMed  Google Scholar 

  29. Kim JH, Chu SC, Gramlich JL, Pride YB, Babendreier E, Chauhan D et al. Activation of the PI3K/mTOR pathway by BCR-ABL contributes to increased production of reactive oxygen species. Blood 2005; 105: 1717–1723.

    Article  CAS  PubMed  Google Scholar 

  30. Sattler M, Verma S, Shrikhande G, Byrne CH, Pride YB, Winkler T et al. The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells. J Biol Chem 2000; 275: 24273–24278.

    Article  CAS  PubMed  Google Scholar 

  31. Rodrigues MS, Reddy MM, Sattler M . Cell cycle regulation by oncogenic tyrosine kinases in myeloid neoplasias: from molecular redox mechanisms to health implications. Antioxid Redox Signal 2008; 10: 1813–1848.

    Article  CAS  PubMed  Google Scholar 

  32. Koptyra M, Falinski R, Nowicki MO, Stoklosa T, Majsterek I, Nieborowska-Skorska M et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 2006; 108: 319–327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chesney J, Mitchell R, Benigni F, Bacher M, Spiegel L, Al-Abed Y et al. An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect. Proc Natl Acad Sci USA 1999; 96: 3047–3052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chesney J, Telang S, Yalcin A, Clem A, Wallis N, Bucala R . Targeted disruption of inducible 6-phosphofructo-2-kinase results in embryonic lethality. Biochem Biophys Res Commun 2005; 331: 139–146.

    Article  CAS  PubMed  Google Scholar 

  35. Nakajima H, Raben N, Hamaguchi T, Yamasaki T . Phosphofructokinase deficiency; past, present and future. Curr Mol Med 2002; 2: 197–212.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported in part by the National Institutes of Health grant (CA134660-03, MS). RLL is a Geoffrey Beene Junior Chair.

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Authors and Affiliations

  1. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA

    M M Reddy, M S Fernandes, A Deshpande, E Weisberg, J D Griffin & M Sattler

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    M M Reddy, M S Fernandes, A Deshpande, E Weisberg, J D Griffin & M Sattler

  3. Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA, USA

    H V Inguilizian & A L Kung

  4. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    O Abdel-Wahab & R L Levine

  5. Department of Medicine, Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA,

    O Abdel-Wahab & R L Levine

  6. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    A L Kung

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  1. M M Reddy
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Correspondence to M Sattler.

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Reddy, M., Fernandes, M., Deshpande, A. et al. The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity. Leukemia 26, 481–489 (2012). https://doi.org/10.1038/leu.2011.225

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