title: Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey.
abstract: 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.
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Germany. germeshausen.manuela@mh-hannover.de
authors.forename: Manuela
authors.initials: M
authors.lastname: Germeshausen
authors.forename: Matthias
authors.initials: M
authors.lastname: Ballmaier
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000741:Anemia, Aplastic / Q000235:genetics; D019090:Case Management; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D018450:Disease Progression; D004198:Disease Susceptibility; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use; D006410:Hematopoiesis; D006801:Humans; D007938:Leukemia / Q000209:etiology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016296:Mutagenesis; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000235:genetics; D009503:Neutropenia / Q000151:congenital / Q000235:genetics*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology
chemical_list: C517047:CSF3R protein, human; D018389:Codon, Nonsense; D012333:RNA, Messenger; D016184:Receptors, Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor