Abstract

Pegylated interferon-α (peg-IFNa) treatment induces molecular responses (MR) in patients with myeloproliferative neoplasms (MPNs), including partial MR (PMR) in 30–40% of patients. Here, we compared the efficacy of IFNa treatment in JAK2V617F- vs. calreticulin (CALR)-mutated cells and investigated the mechanisms of differential response. Retrospective analysis of MPN patients treated with peg-IFNa demonstrated that patients harboring the JAK2V617F mutation were more likely to achieve PMR than those with mutated CALR (p = 0.004), while there was no significant difference in hematological response. In vitro experiments confirmed an upregulation of IFN-stimulated genes in JAK2V617F-positive 32D cells as well as patient samples (peripheral blood mononuclear cells and CD34+ hematopoietic stem cells) compared to their CALR-mutated counterparts, and higher IFNa doses were needed to achieve the same IFNa response in CALR− as in JAK2V617F-mutant 32D cells. Additionally, Janus-activated kinase-1 (JAK1) and signal transducers and activators of transcription 1 (STAT1) showed constitutive phosphorylation in JAK2V617F-mutated but not CALR-mutated cells, indicating priming towards an IFNa response. Moreover, IFN-induced growth arrest was counteracted by selective JAK1 inhibition but enhanced by JAK2 inhibition. In conclusion, our data suggest that, clinically, higher doses of IFNa are needed in CALR-mutated vs. JAK2V617F-positive patients and we suggest a model of JAK2V617F-JAK1/STAT1 crosstalk leading to a priming of JAK2V617F-positive cells to IFNa resulting in differential sensitivity

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Acknowledgements

This work was in part supported by a research grant from the German Research Foundation to SK (DFG KO2155/6-1 and DJCLS 16 R/2017), and by the Core Facility Flow Cytometry, a Core Facility of the Interdisciplinary Center for Clinical Research (IZKF) Aachen within the Faculty of Medicine at RWTH Aachen University. This work was supported by the Chip Facility, a core facility of the Interdisciplinary Center for Clinical Research (IZKF) Aachen within the Faculty of Medicine at RWTH Aachen University. Part of this work was generated within the medical thesis work of JC.

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Author notes

  1. These authors contributed equally: Nicolas Chatain, Steffen Koschmieder.

Affiliations

  1. Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    • Julia Czech
    • , Julian Baumeister
    • , Assja Crepcia
    • , Lijuan Han
    • , Angela Maurer
    • , Claudia Schubert
    • , Kristina Feldberg
    • , Deniz Gezer
    • , Tim H. Brümmendorf
    • , Nicolas Chatain
    •  & Steffen Koschmieder
  2. Department of Hematology, Zealand University Hospital, Copenhagen University Hospital, Roskilde, Denmark

    • Sabrina Cordua
    • , Trine Knudsen
    • , Anders L. Sørensen
    • , Morten Holmström
    • , Lasse Kjær
    • , Vibe Skov
    •  & Hans C. Hasselbalch
  3. Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic

    • Barbora Weinbergerova
    • , Jiri Mayer
    • , Zdenek Racil
    •  & Blanka Kubesova
  4. Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, RWTH Aachen University, Aachen, Germany

    • Tiago Maié
    •  & Ivan G. Costa
  5. Interdisciplinary Center for Clinical Research Aachen Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    • Bernd Denecke
  6. Institute of Pathology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    • Angela Maurer
  7. Institute of Biochemistry and Molecular Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    • Gerhard Müller-Newen
  8. Department of Hematology, Odense University Hospital, Odense, Denmark

    • Thomas Stauffer Larsen

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Conflict of interest

THB has received research funding by and provided consultancy to Pfizer and Novartis. JM has received research support by Novartis and AOP Orphan. HCH reports his participation on the advisory committee of Novartis and AOP Orphan as well as research funding by Novartis. TK got travel support by Novartis in 2016. SK reports funding from Novartis and Bristol-Myers Squibb as well as consultancy honoraria from Novartis, Incyte/Ariad, Bristol-Myers Squibb, AOP, CTI, and Shire. The other authors declare that they have no conflict of interest.

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Correspondence to Steffen Koschmieder.

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https://doi.org/10.1038/s41375-018-0295-6