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GM-CSF treatment is not effective in congenital neutropenia patients due to its inability to activate NAMPT signaling

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Abstract

Severe congenital neutropenia (CN) is a bone marrow failure syndrome characterized by an absolute neutrophil count (ANC) below 500 cells/μL and recurrent, life-threatening bacterial infections. Treatment with granulocyte colony-stimulating factor (G-CSF) increases the ANC in the majority of CN patients. In contrary, granulocyte-monocyte colony-stimulating factor (GM-CSF) fails to increase neutrophil numbers in CN patients in vitro and in vivo, suggesting specific defects in signaling pathways downstream of GM-CSF receptor. Recently, we detected that G-CSF induces granulopoiesis in CN patients by hyperactivation of nicotinamide phosphoribosyl transferase (NAMPT)/Sirtuin 1 signaling in myeloid cells. Here, we demonstrated that, in contrast to G-CSF, GM-CSF failed to induce NAMPT-dependent granulopoiesis in CN patients. We further identified NAMPT signaling as an essential downstream effector of the GM-CSF pathway in myelopoiesis.

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Acknowledgements

We thank the physicians of the Severe Chronic Neutropenia International Registry for providing patient material. We thank study subjects for their cooperation. This work was supported by the Madeleine Schickedanz Kinderkrebs-Stiftung, DFG-SK-92/4, the Excellence Initiative of the Tübingen University, the ERA-Net (e-rare Network of rare diseases), and the Federal Ministry of Education and Research (German Network on Congenital Bone Marrow Failure Syndromes).

Author contributions

C. K., K. W., J. S., and L. K. made the initial observations, designed the experiments, analyzed the data, supervised experimentation, and wrote the manuscript; B. S., T.M. and P.M. performed the experiments; and C. Z. provided patients’ material and patients’ information.

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Authors and Affiliations

  1. Department of Molecular Hematopoiesis, Hannover Medical School, Hannover, Germany

    Corinna Koch & Cornelia Zeidler

  2. Department of Hematology, Oncology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Tübingen, Germany

    Bardia Samareh, Tatsuya Morishima, Perihan Mir, Lothar Kanz & Julia Skokowa

  3. Department of Hematology, Oncology and Bone Marrow Transplantation, Children’s Hospital, University Hospital Tübingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany

    Karl Welte

Authors
  1. Corinna Koch
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  2. Bardia Samareh
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  3. Tatsuya Morishima
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  8. Karl Welte
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Correspondence to Karl Welte.

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Approval for this study was obtained from the Hannover Medical School’s Institutional Review Board, and informed consent was obtained in accordance with the Declaration of Helsinki.

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The authors declare that they have no conflict of interest.

Additional information

Julia Skokowa and Karl Welte contributed as senior authors equally to this work.

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Koch, C., Samareh, B., Morishima, T. et al. GM-CSF treatment is not effective in congenital neutropenia patients due to its inability to activate NAMPT signaling. Ann Hematol 96, 345–353 (2017). https://doi.org/10.1007/s00277-016-2894-5

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  • DOI: https://doi.org/10.1007/s00277-016-2894-5

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