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.

  • Letter to the Editor
  • Published:

The JAK inhibitor ruxolitinib impairs dendritic cell migration via off-target inhibition of ROCK

Leukemia volume 30, pages 2119–2123 (2016)Cite this article

Subjects

Myeloproliferative neoplasms (MPNs) are clonal neoplastic disorders of haematopoiesis, leading to a hypercellular bone marrow and eventually to severe fibrosis, termed myelofibrosis (MF).1 Particularly advanced stage MF patients suffer from splenomegaly, anaemia and constitutional symptoms due to elevated levels of proinflammatory cytokines. A gain-of-function V617F mutation in the JAK2 kinase causes the constitutive activation of the JAK/STAT pathway and is supposed to be at least in part responsible for the disease phenotype of MPN. As the mutation is present in 65% of primary MF patients, 95% of polycythemia vera (PV) patients and 55% of essential thrombocythemia (ET) patients, various JAK inhibitors are currently tested as targeted therapeutics in MPN.2

Ruxolitinib is an oral JAK inhibitor recently approved for treatment of primary and secondary MF that shows impressive symptom control by suppression of inflammation irrespective of the JAK mutational status. Moreover, ruxolitinib is also a promising drug for acute and chronic GvHD treatment.3, 4 We recently described various aspects of immune modulation by ruxolitinib5, 6 including impaired DC function.7

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

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

References

  1. Tefferi A . Myelofibrosis with myeloid metaplasia. N Engl J Med 2000; 342: 1255–1265.

    Article  CAS  Google Scholar 

  2. Percy MJ, McMullin MF . The V617F JAK2 mutation and the myeloproliferative disorders. Hematol Oncol 2005; 23: 91–93.

    Article  CAS  Google Scholar 

  3. Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia 2015; 29: 2062–2068.

    Article  CAS  Google Scholar 

  4. Spoerl S, Mathew NR, Bscheider M, Schmitt-Graeff A, Chen S, Mueller T et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 2014; 123: 3832–3842.

    Article  CAS  Google Scholar 

  5. Parampalli Yajnanarayana S, Stübig T, Cornez I, Alchalby H, Schönberg K, Rudolph J et al. JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms. Br J Haematol 2015; 169: 824–833.

    Article  CAS  Google Scholar 

  6. Schönberg K, Rudolph J, Vonnahme M, Parampalli Yajnanarayana S, Cornez I, Hejazi M et al. JAK inhibition impairs NK cell function in myeloproliferative neoplasms. Cancer Res 2015; 75: 2187–2199.

    Article  Google Scholar 

  7. Heine A, Held SAE, Daecke SN, Wallner S, Yajnanarayana SP, Kurts C et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 2013; 122: 1192–1202.

    Article  CAS  Google Scholar 

  8. Randolph GJ, Angeli V, Swartz MA . Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol 2005; 5: 617–628.

    Article  CAS  Google Scholar 

  9. Sallusto F, Schaerli P, Loetscher P, Schaniel C, Lenig D, Mackay CR et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol 1998; 28: 2760–2769.

    Article  CAS  Google Scholar 

  10. Förster R, Schubel A, Breitfeld D, Kremmer E, Renner-Müller I, Wolf E et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 1999; 99: 23–33.

    Article  Google Scholar 

  11. Stein JV, Soriano SF, M’Rini C, Nombela-Arrieta C, De Buitrago GG, Rodríguez-Frade JM et al. CCR7-mediated physiological lymphocyte homing involves activation of a tyrosine kinase pathway. Blood 2003; 101: 38–44.

    Article  CAS  Google Scholar 

  12. Lämmermann T, Bader BL, Monkley SJ, Worbs T, Wedlich-Söldner R, Hirsch K et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 2008; 453: 51–55.

    Article  Google Scholar 

  13. Zhou T, Georgeon S, Moser R, Moore DJ, Caflisch A, Hantschel O . Specificity and mechanism-of-action of the JAK2 tyrosine kinase inhibitors ruxolitinib and SAR302503 (TG101348). Leukemia 2014; 28: 404–407.

    Article  CAS  Google Scholar 

  14. Vicente-Manzanares M, Ma X, Adelstein RS, Horwitz AR . Non-muscle myosin II takes centre stage in cell adhesion and migration. Nat Rev Mol Cell Biol 2009; 10: 778–790.

    Article  CAS  Google Scholar 

  15. Nitschké M, Aebischer D, Abadier M, Haener S, Lucic M, Vigl B et al. Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation. Blood 2012; 120: 2249–2258.

    Article  Google Scholar 

Download references

Acknowledgements

We thank all the volunteer blood donors and gratefully acknowledge the excellent technical help of Solveig Daecke. This work was in part supported by the Deutsche Forschungsgemeinschaft (DFG WO1877/1-1) for DW.

Author contributions

JR, TQ, JT and AH performed experiments, JR, TQ, AH and DW analysed results and made the figures, PB and WK provided infrastructure, JR and DW designed the project and wrote the manuscript. All authors read and approved the final version of the manuscript.

Author information

Authors and Affiliations

  1. Medical Clinic 3, Oncology, Hematology, Immunoncology and Rheumatology, University Clinic Bonn (UKB), Bonn, Germany

    J Rudolph, A Heine, P Brossart & D Wolf

  2. Molecular Immunology & Cell Biology, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany

    T Quast & W Kolanus

  3. Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany

    J Trebicka

Authors
  1. J Rudolph
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Heine
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Quast
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W Kolanus
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Trebicka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P Brossart
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Wolf.

Ethics declarations

Competing interests

DW, AH, PB received research funding and honoraria from Novartis. JT was supported by Deutsche Forschungsgemeinschaft (SFB TRR57), as well as from grants of H.J. & W. Hector Stiftung.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rudolph, J., Heine, A., Quast, T. et al. The JAK inhibitor ruxolitinib impairs dendritic cell migration via off-target inhibition of ROCK. Leukemia 30, 2119–2123 (2016). https://doi.org/10.1038/leu.2016.155

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2016.155

This article is cited by

Search

Advanced search

Quick links