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Mutations of epigenetic regulators and of the spliceosome machinery in therapy-related myeloid neoplasms and in acute leukemias evolved from chronic myeloproliferative diseases

Leukemia volume 27, pages 982–985 (2013)Cite this article

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Therapy-related myeloid neoplasms (t-MN), including acute myeloid leukemias (t-AML) and myelodysplastic syndromes (t-MDS), indicate myeloid disorders developing in patients treated with radiotherapy and/or chemotherapy for cancer or autoimmune diseases. t-MN represent a unique model of in vivo poison-induced leukemogenesis. It displays a high incidence of monosomies, complex karyotypes and p53 mutations, but other AML-associated mutations, as FLT3, NPM1, CEBPA and TET2 (ten-eleven-translocation 2), are usually rare.1, 2, 3 In addition, t-MN have been shown to display significant changes in gene expression, including upregulation or downregulation of pathways involved in major cellular processes, which are present long before the development of the t-MN and may be expression of early progenitor damage.4 These changes are due to the synergistic negative effects of previous treatments, probably in the presence of individual predisposing factors, and finally result into leukemic transformation.

Epigenetic deregulation of gene expression is one of the main pathogenetic processes in AML and MDS. High rates of gene-specific methylation have been reported in these diseases,5, 6, 7 but the underlying mechanisms are poorly understood. The identification of mutations in several genes involved in epigenetic regulation has given new insights. Among these, recurrent somatic mutations of enzymes involved in methylation, including DNMT3A (DNA methyltransferase 3A), IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2), TET2 and EZH2 (enhancer of Zeste homolog 2, Drosophila), have been described in about 10–20% of de novo AML.

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References

  1. Leone G, Fianchi L, Voso MT . Therapy-related myeloid neoplasms. Curr Opin Oncol 2011; 23: 672–680.

    Article  CAS  Google Scholar 

  2. Kosmider O, Delabesse E, de Mas VM, Cornillet-Lefebvre P, Blanchet O, Delmer A et al. TET2 mutations in secondary acute myeloid leukemias: a French retrospective study. Haematologica 2011; 96: 1059–1063.

    Article  CAS  Google Scholar 

  3. D'Alò F, Fianchi L, Fabiani E, Criscuolo M, Greco M, Guidi F et al. Similarities and differences between therapy-related and elderly acute myeloid leukemia. Mediterr J Hematol Infect Dis 2011; 3: e2011052.

    Article  Google Scholar 

  4. Tsai HC, Li H, Van Neste L, Cai Y, Robert C, Rassool FV et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 2012; 21: 430–446.

    Article  CAS  Google Scholar 

  5. Figueroa ME, Skrabanek L, Li Y, Jiemjit A, Fandy TE, Paietta E et al. MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation. Blood 2009; 114: 3448–3458.

    Article  CAS  Google Scholar 

  6. Jiang Y, Dunbar A, Gondek LP, Mohan S, Rataul M, O'Keefe C et al. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood 2009; 113: 1315–1325.

    Article  CAS  Google Scholar 

  7. Greco M, D'Alò F, Scardocci A, Criscuolo M, Fabiani E, Guidi F et al. Promoter methylation of DAPK1, E-cadherin and thrombospondin-1 in de novo and therapy-related myeloid neoplasms. Blood Cells Mol Dis 2010; 45: 181–185.

    Article  CAS  Google Scholar 

  8. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011; 478: 64–69.

    Article  CAS  Google Scholar 

  9. Malcovati L, Papaemmanuil E, Bowen DT, Boultwood J, Della Porta MG, Pascutto C et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood 2011; 118: 6239–6246.

    Article  CAS  Google Scholar 

  10. Fried I, Bodner C, Pichler MM, Lind K, Beham-Schmid C, Quehenberger F et al. Frequency, onset and clinical impact of somatic DNMT3A mutations in therapy-related and secondary acute myeloid leukemia. Haematologica 2012; 97: 246–250.

    Article  CAS  Google Scholar 

  11. Ottone T, Cicconi L, Hasan SK, Lavorgna S, Divona M, Voso MT et al. Comparative molecular analysis of therapy-related and de novo acute promyelocytic leukemia. Leuk Res 2012; 36: 474–478.

    Article  CAS  Google Scholar 

  12. Tefferi A, Lasho TL, Abdel-Wahab O, Guglielmelli P, Patel J, Caramazza D et al. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia 2010; 24: 1302–1309.

    Article  CAS  Google Scholar 

  13. Zhang SJ, Rampal R, Manshouri T, Patel J, Mensah N, Kayserian A et al. Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. Blood 2012; 119: 4480–4485.

    Article  CAS  Google Scholar 

  14. Finazzi G, Caruso V, Marchioli R, Capnist G, Chisesi T, Finelli C et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood 2005; 105: 2664–2670.

    Article  CAS  Google Scholar 

  15. Kiladjian JJ, Chevret S, Dosquet C, Chomienne C, Rain JD . Treatment of polycythemia vera with hydroxyurea and pipobroman: final results of a randomized trial initiated in 1980. J Clin Oncol 2011; 29: 3907–3913.

    Article  Google Scholar 

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Acknowledgements

This work was supported by grants from Associazione Italiana Ricerca sul Cancro (AIRC) and FIRB (RBAP11TF7Z).

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  1. Istituto di Ematologia, Università Cattolica Sacro Cuore, Rome, Italy

    M T Voso, E Fabiani, L Fianchi, G Falconi, M Criscuolo, R Santangelo, P Chiusolo, S Betti, F D'Alo', S Hohaus, V De Stefano & G Leone

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  1. M T Voso
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Correspondence to M T Voso.

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Voso, M., Fabiani, E., Fianchi, L. et al. Mutations of epigenetic regulators and of the spliceosome machinery in therapy-related myeloid neoplasms and in acute leukemias evolved from chronic myeloproliferative diseases. Leukemia 27, 982–985 (2013). https://doi.org/10.1038/leu.2012.267

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