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:

Rare germline variants in regions of loss of heterozygosity may influence clinical course of hematological malignancies

Leukemia volume 25, pages 1782–1784 (2011)Cite this article

Subjects

Somatically acquired uniparental disomy (UPD) has been recognized as a common mechanism of mutation amplification in cancer. Somatic heterozygous mutations can become homozygous if the chromosomal arm harboring the mutation undergoes mitotic recombination and two chromosomes carrying the mutation segregate into the same daughter cell. As a result, UPD occurs, accompanied by loss of heterozygosity from the recombination breakpoint to the telomere of the affected chromosomal arm. UPD of chromosome 9p is a frequent event in myeloproliferative neoplasms and was found to be associated with the oncogenic V617F mutation of the JAK2 gene.1 A number of other UPDs were shown to amplify heterozygous mutations in genes such as MPL, CBL and EZH2 in myeloid malignancies.2, 3, 4

Fanconi anemia is a heterogeneous hereditary blood disorder characterized by early onset anemia, cancer predisposition and various congenital abnormalities. The male polycythemia vera patient who carried the R658X mutation of FANCM was diagnosed in December 1993 at age of 44 as polycythemia vera with a hematocrit of 66.6% and serum erythropoietin levels below detection limit. The patient was positive for the JAK2-V617F mutation and required regular phlebotomies. In September 2000, the patient presented with increased leukocyte count (17.5 × 109/l). Between September and November 2003, the patient was in a plateau phase without a need of phlebotomies. In January 2004, the patient presented first time with anemia and 1% of blasts in the peripheral blood. The patient required transfusions since January 2005. We sampled the patient in September 2006 for the karyotype analysis, using the SNP 6.0 mapping arrays (Affymetrix, Santa Clara, CA, USA). The patient exhibited 9pUPD with high JAK2-V617F mutation burden and 14qUPD, but no other chromosomal aberrations. At this sampling date, the patient was anemic (hemoglobin 6.8 g/l) with 2% blasts in peripheral blood, had a leukocyte count of 25.2 × 109/l and a marked thrombocytosis (platelet count 3753 × 109/l). The blast count increased continuously (14% in June 2007), consistent with transformation to acute myeloid leukemia that was confirmed in October 2007. The patient died in April 2009.

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 Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2

References

  1. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779–1790.

    Article  CAS  Google Scholar 

  2. Kawamata N, Ogawa S, Yamamoto G, Lehmann S, Levine RL, Pikman Y et al. Genetic profiling of myeloproliferative disorders by single-nucleotide polymorphism oligonucleotide microarray. Exp Hematol 2008; 36: 1471–1479.

    Article  CAS  Google Scholar 

  3. Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature 2009; 460: 904–908.

    Article  CAS  Google Scholar 

  4. Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 2010; 42: 722–726.

    Article  CAS  Google Scholar 

  5. Meetei AR, Medhurst AL, Ling C, Xue Y, Singh TR, Bier P et al. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet 2005; 37: 958–963.

    Article  CAS  Google Scholar 

  6. Klampfl T, Harutyunyan A, Berg T, Gisslinger B, Schalling M, Bagienski K et al. Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression. Blood 2011; e-pub ahead of print 29 April 2011; doi:10.1182/blood-2011-01-331678.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The study was supported by funding from the Austrian Academy of Sciences, the Austrian Science Fund (FWF) and the MPN Research Foundation.

Author information

Authors and Affiliations

  1. Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    A Harutyunyan, T Klampfl, T Berg, K Bagienski & R Kralovics

  2. Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria

    B Gisslinger, H Gisslinger & R Kralovics

Authors
  1. A Harutyunyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B Gisslinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Klampfl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Berg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Bagienski
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Gisslinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R Kralovics
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R Kralovics.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harutyunyan, A., Gisslinger, B., Klampfl, T. et al. Rare germline variants in regions of loss of heterozygosity may influence clinical course of hematological malignancies. Leukemia 25, 1782–1784 (2011). https://doi.org/10.1038/leu.2011.150

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.150

This article is cited by

Search

Advanced search

Quick links