Blood Journal
Leading the way in experimental and clinical research in hematology

Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: results of a long-term survey

  1. Manuela Germeshausen1,
  2. Matthias Ballmaier1, and
  3. Karl Welte1
  1. 1Department of Pediatric Hematology and Oncology, Hannover Medical School, Germany


Point mutations in the gene for the granulocyte colony-stimulating factor (G-CSF) receptor CSF3R have been implicated in the progression of severe congenital neutropenia (CN) to leukemia. In this study we present data on a total of 218 patients with chronic neutropenia, including 148 patients with CN (23/148 with secondary malignancies). We detected CSF3R nonsense mutations at 17 different nucleotide positions (thereof 10 new mutations) which lead to a loss of 1 to all 4 tyrosine residues in the intracellular domain of the receptor. Of 23 patients with CN with signs of malignant transformation, 18 (78%) were shown to harbor a CSF3R mutation, indicating that these mutations, although not a necessary condition, are highly predictive for malignant transformation even if detected in a low percentage of transcripts. In serial analyses of 50 patients with CSF3R mutations we were able to follow the clonal dynamics of mutated cells. We could demonstrate that even a highly clonal hematopoiesis did not inevitably show a rapid progression to leukemia. Our results strongly suggest that acquisition of a CSF3R mutation is an early event in leukemogenesis that has to be accompanied by cooperating molecular events, which remain to be defined.

  • Submitted February 17, 2006.
  • Accepted August 9, 2006.
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