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Growth Factors

An acquired G-CSF receptor mutation results in increased proliferation of CMML cells from a patient with severe congenital neutropenia

Leukemia volume 19, pages 611–617 (2005)Cite this article

Abstract

Severe congenital neutropenia (CN) is characterized by a maturation arrest of myelopoiesis at the promyelocyte stage. Treatment with pharmacological doses of recombinant human granulocyte colony-stimulating factor (rh-G-CSF) stimulates neutrophil production and decreases the risk of major infectious complications. However, approximately 15% of CN patients develop myeloid malignancies that have been associated with somatic mutations in the G-CSF receptor (G-CSFR) and RAS genes as well as with acquired monosomy 7. We report a CN patient with chronic myelomonocytic leukemia (CMML) who never received rh-G-CSF. Molecular analysis demonstrated a somatic G-CSFR mutation (C2390T), which led to expression of a truncated G-CSFR protein in the CMML. Normal G-CSFR expression was unexpectedly absent in primary and cultured CMML. In addition, CMML cells showed monosomy 7 and an oncogenic NRAS mutation. In vitro culture revealed a G-CSF-dependent proliferation of CMML cells, which subsequently differentiated along the monocytic/macrophage lineage. Our results provide direct evidence for the in vivo expression of a truncated G-CSFR in leukemic cells, which emerged in the absence of rh-G-CSF treatment and transduces proliferative signals.

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Acknowledgements

We thank Sabine Jakobs and Klara Cherkaoui for excellent technical assistance and Gernot Beutel for his help with the microscopic pictures. The work was supported, in part, by Deutsche Krebshilfe (10-1548-We2) and by NIH Grant R01 CA72614.

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Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, Hannover Medical School, Germany

    M Germeshausen, K Welte & M Ballmaier

  2. Departments of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    H Schulze

  3. Department of Pediatrics, University of California, San Francisco, CA, USA

    C Kratz & K Shannon

  4. Department of Cell and Molecular Pathology, Hannover Medical School, Germany

    L Wilkens

  5. Department of Hematology and Oncology, University of Erlangen-Nürnberg, Erlangen, Germany

    R Repp

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  1. M Germeshausen
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Correspondence to M Germeshausen.

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Germeshausen, M., Schulze, H., Kratz, C. et al. An acquired G-CSF receptor mutation results in increased proliferation of CMML cells from a patient with severe congenital neutropenia. Leukemia 19, 611–617 (2005). https://doi.org/10.1038/sj.leu.2403663

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