Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor

Abstract

ACUTE lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Despite the progress achieved in its treatment, 20% of cases relapse and no longer respond to chemotherapy. The most common phenotype of ALL cells share surface antigens with very early precursors of B cells and are therefore believed to originate from this lineage1,3Characterization of the growth requirement of ALL cells indicated that they were dependent on various cytokines, suggesting paracrine and/or autocrine growth regulation4–6. Because many cytokines induce tyrosine phosphorylation in lymphoid progenitor cells, and constitutive tyrosine phosphorylation is commonly observed in B-lineage leukaemias7,8, attempts have been made to develop protein tyrosine kinase (PTK) blockers of leukaemia cell growth9,10. Here we show that leukaemic cells from patients in relapse have con-stitutively activated Jak-2 PTK. Inhibition of Jak-2 activity by a specific tyrosine kinase blocker, AG-490, selectively blocks leukaemic cell growthin vitro and in vivo by inducing programmed cell death, with no deleterious effect on normal haematopoiesis.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

References

  1. Nadler, L. M. et al. J. Immun. 131, 244–250 (1983).

    CAS  PubMed  Google Scholar 

  2. Greaves, M. F. Science 234, 697–704 (1986).

    Article  ADS  CAS  Google Scholar 

  3. Uckun, F. M. et al. New Engl. J. Med. 329, 1296–1301 (1993).

    Article  CAS  Google Scholar 

  4. Williams, G. T., Smith, C. A., Spooncer, E., Dexter, T. M. & Jaylor, D. R. Nature 343, 76–79 (1990).

    Article  ADS  CAS  Google Scholar 

  5. Cohen, A. et al. Blood 78, 94–102 (1991).

    CAS  PubMed  Google Scholar 

  6. Touw, J. et al. Blood 75, 2097–2101 (1990).

    CAS  PubMed  Google Scholar 

  7. Grimaldi, J. C. & Meeker, T. C. Blood 73, 2081–2085 (1989).

    CAS  PubMed  Google Scholar 

  8. Dadi, H., Ke, S. & Roifman, C. M. Biochem. biophys. Res. Commun. 192, 459–464 (1993).

    Article  CAS  Google Scholar 

  9. Burke, T. et al. J. med. Chem. 36, 425–432 (1993).

    Article  CAS  Google Scholar 

  10. Cushman, M. et al. J. med. Chem. 37, 3353–3362 (1994).

    Article  CAS  Google Scholar 

  11. Osherove, N. & Levitzki, A. Eur. J. Biochem. 225, 1047–1053 (1994).

    Article  Google Scholar 

  12. Padeh, S., Levitzki, A., Gazit, A., Mills, G. & Roifman, C. M. J. clin Invest. 87, 1114–1118 (1991).

    Article  CAS  Google Scholar 

  13. Osamu, M. et al. Blood 84, 1501–1507 (1994).

    Google Scholar 

  14. Sato, M. et al. J. exp. Med. 180, 2101–211 (1994).

    Article  CAS  Google Scholar 

  15. Barber, D. L. & D'Andrea, A. D. Molec. cell. Biol. 14, 6506–6514 (1994).

    Article  CAS  Google Scholar 

  16. Tanaka, N. et al. Proc. natn. Acad. Sci. U.S.A. 91, 7271–7275 (1994).

    Article  ADS  CAS  Google Scholar 

  17. Johnston, J. A. et al. Nature 370, 151–153 (1994).

    Article  ADS  CAS  Google Scholar 

  18. Witthuhn, B. A. et al. Nature 370, 153–157 (1994).

    Article  ADS  CAS  Google Scholar 

  19. Roifman, C. M., Wang, G., Freedman, M. & Pan, Z. J. Immun. 148, 1136–1142 (1992).

    CAS  PubMed  Google Scholar 

  20. Wilks, A. F. et al. Molec. cell. Biol. 11, 2057–2065 (1991).

    Article  CAS  Google Scholar 

  21. Harpur, A. G. Andres, A-C., Ziemiecki, A., Aston, R. R. & Wilkes A. F. Oncogene 7, 1347–1353 (1992).

    CAS  Google Scholar 

  22. Rothman, P. et al. Immunity 1, 457–468 (1994).

    Article  CAS  Google Scholar 

  23. Bolen, J. B., Thompson, P. A., Eiseman, E. & Horak, I. D. Adv. Cancer Res. 57, 103–149 (1991).

    Article  CAS  Google Scholar 

  24. Bolen, J. B. et al. FASEB J. 6, 3403–3409 (1992).

    Article  CAS  Google Scholar 

  25. Estrov, Z. & Freedman, M. H. Expl Hemat. 19, 221–225 (1991).

    CAS  Google Scholar 

  26. Schmid, I., Uittenbogaart, C. H. & Giorgi, J. V. Cytometry 15, 12–20 (1994).

    Article  CAS  Google Scholar 

  27. Uckun, F. M. et al. Science 267, 886–891 (1995).

    Article  ADS  CAS  Google Scholar 

  28. Kamel-Reid, S. et al. Science 246, 1597–1600 (1989).

    Article  ADS  CAS  Google Scholar 

  29. Kamel-Reid, S. et al. Leukemia 6, 8–17 (1992).

    CAS  PubMed  Google Scholar 

  30. Arpaia, E., Shahar, M., Dadi, H., Cohen, A. & Roifman, C. M. Cell 76, 947–958 (1994).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Meydan, N., Grunberger, T., Dadi, H. et al. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379, 645–648 (1996). https://doi.org/10.1038/379645a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/379645a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing