DNMT3A mutations in myeloproliferative neoplasms (original) (raw)

Leukemia volume 25, pages 1217–1219 (2011)Cite this article

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Since the discovery of the gain-of-function mutation JAK2 V617F in 2005, an increasing number of mutations have been described in myeloproliferative neoplasms (MPN) and related myeloid malignancies.1, 2, 3, 4 For instance, use of array-based techniques such as comparative genomic hybridization and single-nucleotide polymorphism (SNP) analysis led to the identification of genes involved in epigenetic regulation such as tet-oncogene family member 2 (TET2), additional sex combs like 1 (ASXL1) and enhancer of zeste 2 (EZH2).5, 6, 7 Inactivating mutations in TET2, ASXL1 and EZH2 are considered to promote myeloid tumorigenesis because of epigenetic modulation of target genes. More recently, a whole-genome sequencing study in acute myeloid leukemia (AML) uncovered recurrent mutations in 22% of AML patients in another epigenetic regulator, the DNA methyltransferase 3A gene DNMT3A.8 In this study, DNMT3A mutations were associated with poor outcome and, thus, are of clinical relevance. However, exact mechanisms of action of DNMT3A mutations are still unclear because global methylation patterns and 5-methylcytosine content in AML genomes were not significantly altered. Nevertheless, mutations of TET2, ASXL1, EZH2 and DNMT3A occur in a significant number of patients with myeloid malignancies underlining the pathogenic relevance of epigenetic changes.

On the basis of these findings we sought to explore the mutation frequency of DNMT3A in a series of well-characterized ‘classic’ MPN cases. In our study, 115 chronic- (_n_=80) or blast-phase (_n_=35) MPN cases were screened for DNMT3A mutations using direct DNA sequencing of all coding exons (2–23): essential thrombocythemia (ET), _n_=30; polycythemia vera (PV), _n_=30; primary myelofibrosis, _n_=16; post-ET MF, _n_=2; post-PV MF, _n_=2; AML secondary to MPN (sAML), _n_=35. In chronic-phase MPN, DNA from peripheral blood granulocytes was analyzed, whereas mononuclear cell DNA from bone marrow (_n_=9) or peripheral blood (_n_=26) was used in sAML cases. Mutation data on JAK2 V617F, MPL W515L, TET2 (exon 3–11), IDH1/2 (exons 4), ASXL1 (exon 12), CBL (exon 8–9) and EZH2 (exon 2–20) were available in all cases. Technical details on mutation assays are available on request. In addition, all cases were analyzed on Affymetrix (Santa Clara, CA, USA) 250K SNP arrays allowing for genome-wide screening of copy number alterations and uniparental disomies at high resolution. All patients gave written informed consent for molecular analyses. The study was approved by the Ethics Committee of the University Hospital of Ulm.

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References

  1. Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006; 3: e270.
    Article Google Scholar
  2. Grand FH, Hidalgo-Curtis CE, Ernst T, Zoi K, Zoi C, McGuire C et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood 2009; 113: 6182–6192.
    Article CAS Google Scholar
  3. Carbuccia N, Murati A, Trouplin V, Brecqueville M, Adélaïde J, Rey J et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 2009; 23: 2183–2186.
    Article CAS Google Scholar
  4. Oh ST, Simonds EF, Jones C, Hale MB, Goltsev Y, Gibbs Jr KD et al. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood 2010; 116: 988–992.
    Article CAS Google Scholar
  5. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360: 2289–2301.
    Article Google Scholar
  6. Gelsi-Boyer V, Trouplin V, Adélaïde J, Bonansea J, Cervera N, Carbuccia N et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol 2009; 145: 788–800.
    Article CAS Google Scholar
  7. 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
  8. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363: 2424–2433.
    Article CAS Google Scholar

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Acknowledgements

This study was supported by a grant from the Else Kröner-Fresenius-Stiftung (project P28/07//A56/07); LB was supported in part by the Deutsche Forschungsgemeinschaft (BU 1339/3-1).

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Authors and Affiliations

  1. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
    F Stegelmann, L Bullinger, R F Schlenk, P Paschka, C Blersch, S Kuhn, S Schauer, H Döhner & K Döhner
  2. Department of Hematology and Oncology, Johannes Wesling Klinikum Minden, Minden, Germany
    M Griesshammer

Authors

  1. F Stegelmann
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  2. L Bullinger
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  3. R F Schlenk
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  4. P Paschka
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  5. M Griesshammer
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  6. C Blersch
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  7. S Kuhn
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  8. S Schauer
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  9. H Döhner
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  10. K Döhner
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Correspondence toK Döhner.

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Stegelmann, F., Bullinger, L., Schlenk, R. et al. DNMT3A mutations in myeloproliferative neoplasms.Leukemia 25, 1217–1219 (2011). https://doi.org/10.1038/leu.2011.77

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