Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

The c-kit (CD117) sequence variation M541L, but not N564K, is frequent in the general population, and is not associated with CML in Caucasians

Leukemia volume 20, pages 354–355 (2006)Cite this article

Recently, Inokuchi et al.1 reported the potential clinical significance of two sequence variations of the c-kit oncoprotein: a conservative amino-acid exchange from methionine to leucine in the transmembrane domain at codon 541 (c.1621A>C, p.M541L [exon 10]) and an asparagine to lysine substitution in the juxtamembrane domain at codon 564 (c.1692T>G, p.N564K [exon 11]) in patients with chronic myelogenous leukemia (CML) from Japan. They found 541Leu to be significantly more frequent in CML patients (six out of 80, 7.5%) than in healthy controls (one out of 68, 1.5%; P<0.05, Fisher's exact test). 564Lys was present in one out of the 80 CML patients (1.3%) and in none of the 68 healthy controls. In order to examine functional differences between these sequence variants and wild-type c-kit, an in vitro assay was performed. The authors generated murine KITL540 and KITK563 expression vectors, which were introduced into interleukin-3 (IL-3)-dependent murine Ba/F3 cells to study their state of tyrosine phosphorylation and growth rate after treatment with increasing concentrations of recombinant mouse stem cell factor (rmSCF). The tyrosine kinase activation of KITL540 was slightly higher than that of KITWT in medium containing 0.1 ng/ml SCF, whereas the tyrosine kinase activation of KITK563 was relatively higher than that of KITWT in medium containing between 0.1 and 1.0 ng/ml SCF. Compared to the wild types, the Ba/F3 cell proliferation activity of KITL540 was not increased, whereas the proliferative response of KITK563-expressing cells was higher in medium containing between 0.1 and 1.0 ng/ml SCF. Based on these in vitro data taken from a murine assay and on the significantly higher proportion of 541Leu carriers among CML patients than in healthy controls, the authors suggested that 541Leu is not a polymorphism and speculated that the observed differences in in vitro function may influence the clinical phenotype of CML in humans.1

C-kit (CD117) encodes the transmembrane receptor tyrosine kinase KIT, whose intracellular kinase activity is stimulated after binding of the ligand stem cell factor (SCF) to the extracellular receptor. KIT is expressed in hematopoietic progenitor cells, mast cells, interstitial cells of Cajal (ICCs), germ cells and melanocytes. Gain-of-function mutations result in an SCF-independent tyrosine kinase activity and cause malignancies of each of these cell types, that is, acute myelogenous leukemia (AML), mastocytosis, gastrointestinal stromal tumors (GISTs), germ cell tumors and melanomas (for a review, see reference Akin and Metcalfe2). Loss-of-function mutations of c-kit, in contrast, were shown to cause piebaldism, an autosomal dominantly inherited disorder characterized by congenital patches of white skin and hair that lack melanocytes (for a review, see reference Spritz3).

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Inokuchi K, Yamaguchi H, Tarusawa M, Futaki M, Hanawa H, Tanosaki S et al. Abnormality of c-kit oncoprotein in certain patients with chronic myelogenous leukaemia – potential clinical significance. Leukemia 2002; 16: 170–177.

    Article  CAS  PubMed  Google Scholar 

  2. Akin C, Metcalfe DD . The biology of Kit in disease and the application of pharmacogenetics. J Allergy Clin Immunol 2004; 114: 13–19.

    Article  CAS  PubMed  Google Scholar 

  3. Spritz RA . Molecular basis of human piebaldism. J Invest Dermatol 1994; 103 (5 Suppl): 137S–140S.

    Article  CAS  PubMed  Google Scholar 

  4. Murakami T, Fukai K, Oiso N, Hosomi N, Kato A, Garganta C et al. New KIT mutations in patients with piebaldism. J Dermatol Sci 2004; 35: 29–33.

    Article  CAS  PubMed  Google Scholar 

  5. Cross NC, Melo JV, Feng L, Goldman JM . An optimized multiplex polymerase chain reaction (PCR) for detection of BCR-ABL fusion mRNAs in haematological disorders. Leukemia 1994; 8: 186–189.

    CAS  PubMed  Google Scholar 

  6. Reiter A, Skladny H, Hochhaus A, Seifarth W, Heimpel H, Bartram CR et al. Molecular response of CML patients treated with interferon-alpha monitored by quantitative Southern blot analysis. German chronic myeloid leukaemia (CML) Study Group. Br J Haematol 1997; 97: 86–93.

    Article  CAS  PubMed  Google Scholar 

  7. Nagata H, Worobec AS, Metcalfe DD . Identification of a polymorphism in the transmembrane domain of the protooncogene c-kit in healthy subjects. Exp Clin Immunogenet 1996; 13: 210–214.

    CAS  PubMed  Google Scholar 

  8. Corless CL, Fletcher JA, Heinrich MC . Biology of gastrointestinal stromal tumors. J Clin Oncol 2004; 22: 3813–3825.

    Article  CAS  PubMed  Google Scholar 

  9. Yanagihori H, Oyama N, Nakamura K, Kaneko F . c-kit mutations in patients with childhood-onset mastocytosis and genotype-phenotype correlation. J Mol Diagn 2005; 7: 252–257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ng PC, Henikoff S . Accounting for human polymorphisms predicted to affect protein function. Genome Res 2002; 12: 436–446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Mr A. Schiewart and Ms B. Hanel for excellent technical assistance. This study was supported by the Competence Network ‘Acute and chronic leukemias’, sponsored by the German Bundesministerium für Bildung und Forschung (Projektträger Gesundheitsforschung; DLR e.V.- 01 GI9980/6).

Author information

Author notes

  1. S Krüger

    Present address: Institute of Clinical Genetics, Dresden University of Technology, Dresden, Germany

Authors and Affiliations

  1. Department of Surgical Research, Dresden University of Technology, Dresden, Germany

    S Krüger & H K Schackert

  2. III. Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany

    M Emig & A Hochhaus

  3. Department of Clinical Chemistry – Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany

    P Lohse

  4. I. Department of Internal Medicine, Dresden University of Technology, Dresden, Germany

    G Ehninger

Authors
  1. S Krüger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Emig
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P Lohse
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Ehninger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Hochhaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H K Schackert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Krüger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krüger, S., Emig, M., Lohse, P. et al. The c-kit (CD117) sequence variation M541L, but not N564K, is frequent in the general population, and is not associated with CML in Caucasians. Leukemia 20, 354–355 (2006). https://doi.org/10.1038/sj.leu.2404038

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404038

This article is cited by

Search

Advanced search

Quick links