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Screening for G-CSF receptor mutations in patients with secondary myeloid or lymphoid transformation of severe congenital neutropenia. A report from the French neutropenia register

Leukemia volume 18, pages 1553–1555 (2004)Cite this article

TO THE EDITOR

Severe Congenital Neutropenia (SCN), also referred to as Kostmann's syndrome, is a rare inherited disorder characterized by a profound neutropenia linked to a maturation arrest of myeloid progenitors at the promyelocyte stage and an elevated prevalence (9%) of MDS/AML transformation.1 A group of five acquired nonsense mutations (codons 716, 718, 720, 726 and 731) clustering in the median part of the intracellular domain of the G-CSF receptor (G-CSF-R) has been reported in SCN patients, mainly in those developing secondary MDS or AML.2, 3 All these mutations are C/T transitions introducing a STOP codon resulting in the deletion of the distal intracellular region of the G-CSF-R known to be involved in differentiation signaling.4 Owing to the tight correlation noted between mutation occurrence and leukemic events in SCN patients,2 the acquisition of these G-CSF-R mutations is suspected to be an important step in the leukemogenesis. Overall, 101 SCN patients have been enrolled in the French neutropenia registry, of whom six developed myelodysplasia/acute leukemia. During the course of G-CSF-R mutation screening in SCN patients of the French Neutropenia Registry, four patients were tested at the time they developed secondary malignant transformation. SCN was diagnosed according to previously described criteria (persistent profound neutropenia at a young age together with a maturation arrest of bone marrow myeloid progenitors).1 Total RNA isolated from bone marrow mononuclear cells using the RNAplus reagent (Qbiogen, Illkirch, France) was reverse transcribed and submitted to PCR amplification between nucleotides 2310 and 2530, a fragment encompassing all the previously reported mutations, with forward primer 5′-GCTCAGAGACCTGTGGCCTCCC-3′ and reverse primer 5′-ATAGGACTTGGGGCTGGGGGT-3′. PCR products were analyzed by (1) SSCP analysis performed at 20°C in 12.5% polyacrylamide gels on a Genephor apparatus (Pharmacia Biotech), followed by a sensitive coloration with the DNA Silver Staining kit (Amersham Biosciences, Uppsala, Sweden), (2) restriction enzyme analysis with BfaI enzyme and (3) direct sequencing of purified PCR products. The nucleotide numbering is given according to the reference sequence whose accession number is gb:M59818.

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References

  1. Freedman MH, Bonilla MA, Fier C, Bolyard AA, Scarlata D, Boxer LA et al. Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy. Blood 2000; 96: 429–436.

    CAS  PubMed  Google Scholar 

  2. Dong F, Dale DC, Bonilla MA, Freedman M, Fasth A, Neijens HJ et al. Mutations in the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia. Leukemia 1997; 11: 120–125.

    Article  CAS  PubMed  Google Scholar 

  3. Tidow N, Pilz C, Teichmann B, Muller-Brechlin A, Germeshausen M, Kasper B et al. Clinical relevance of point mutations in the cytoplasmic domain of the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia. Blood 1997; 89: 2369–2375.

    CAS  PubMed  Google Scholar 

  4. Avalos BR . Molecular analysis of the granulocyte colony-stimulating factor receptor. Review. Blood 1996; 88: 761–777.

    CAS  PubMed  Google Scholar 

  5. Dong F, Brynes RK, Tidow N, Welte K, Lowenberg B, Touw IP . Mutations in the gene for the granulocyte colony-stimulating factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia. N Engl J Med 1995; 333: 487–493.

    Article  CAS  PubMed  Google Scholar 

  6. Morikawa K, Morikawa S, Nakamura M, Miyawaki T . Characterization of granulocyte colony-stimulating factor receptor expressed on human lymphocytes. Br J Haematol 2002; 118: 296–304.

    Article  CAS  PubMed  Google Scholar 

  7. Inukai T, Sugita K, Iijima K, Goi K, Tezuka T, Kojika S et al. Leukemic cells with 11q23 translocations express granulocyte colony-stimulating factor (G-CSF) receptor and their proliferation is stimulated with G-CSF. Leukemia 1998; 12: 382–389.

    Article  CAS  PubMed  Google Scholar 

  8. Germeshausen M, Ballmaier M, Schulze H, Welte K, Flohr T, Beiske K et al. Granulocyte colony-stimulating factor receptor mutations in a patient with acute lymphoblastic leukemia secondary to severe congenital neutropenia. Blood 2001; 97: 829–830.

    Article  CAS  PubMed  Google Scholar 

  9. Bernard T, Gale RE, Evans JP, Linch DC . Mutations of the granulocyte-colony stimulating factor receptor in patients with severe congenital neutropenia are not required for transformation to acute myeloid leukaemia and may be a bystander phenomenon. Br J Haematol 1998; 101: 141–149.

    Article  CAS  PubMed  Google Scholar 

  10. Hermans MH, van de Geijn GJ, Antonissen C, Gits J, van Leeuwen D, Ward AC et al. Signaling mechanisms coupled to tyrosines in the granulocyte colony-stimulating factor receptor orchestrate G-CSF-induced expansion of myeloid progenitor cells. Blood 2003; 101: 2584–2590.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work has been supported by grants from the Association pour le Recherche contre le Cancer, and from AFM-Inserm network.

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Authors and Affiliations

  1. Nuclear Medicine Department Hôpital Saint-Louis, Laboratoire de Biologie Cellulaire Hématopoïétique, AP-HP, Paris, France

    B Cassinat, M L Menot & C Chomienne

  2. Biochemistry Department, Molecular Biology Unit, Hôpital Saint-Antoine, Paris

    C Bellanné-Chantelot & C Vaury

  3. Department of Pediatrics, Onco-Hematology Unit, University Hospital, Bordeaux, France

    A Notz-Carrère, M Micheau & Y Perel

  4. Department of Pediatrics, Hôpital du Kremlin-Bicetre, le Kremlin Bicetre, France

    B Bader-Meunier

  5. Department of Pediatrics, Hôpital Saint-Louis, AP-HP, Paris, France

    T Leblanc

  6. Pediatric Hemato-Oncology Department, Hôpital Trousseau, Paris, France

    J Donadieu

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  1. B Cassinat
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Correspondence to B Cassinat.

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Cassinat, B., Bellanné-Chantelot, C., Notz-Carrère, A. et al. Screening for G-CSF receptor mutations in patients with secondary myeloid or lymphoid transformation of severe congenital neutropenia. A report from the French neutropenia register. Leukemia 18, 1553–1555 (2004). https://doi.org/10.1038/sj.leu.2403431

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