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Telomere shortening, clonal evolution and disease progression in myelodysplastic syndrome patients with 5q deletion treated with lenalidomide

Leukemia volume 26, pages 356–358 (2012)Cite this article

Myelodysplastic syndrome (MDS) with del(5q) constitutes a distinct subtype of MDS associated with a favorable prognosis and a relatively low risk of leukemic transformation.1 Lenalidomide, a thalidomide analog with immunomodulatory and anti-angiogenic properties, induced transfusion independence and cytogenetic response in a high proportion of MDS patients with del(5q).2 Thus, treatment with lenalidomide provides a new important therapeutic option for patients with transfusion-dependent anemia. Yet, most patients relapsed after a median of 2 years of treatment and one third of these patients progressed to acute myeloid leukemia. As most of these patients developed complex aberrant karyotypes, genetic instability and clonal evolution seem to be a driving force for the leukemic transformation.3 The mechanisms inducing clonal evolution in MDS patients with del(5q) following the lenalidomide treatment remain obscure. However, small subclones with TP53 mutations were recently identified as a risk factor for leukemic transformation in low-risk del(5q) MDS, if these are primary or secondary events remain to be clarified.4 Further identification of predictive markers identifying patients with increased risk of disease progression would greatly improve patient care.

We reasoned that telomere shortening may be involved in clonal evolution and acute myeloid leukemia progression. Telomeres consist of TTAGGG repeats, which form a specialized nucleoprotein structure (‘T-loop’) that caps the chromosome ends. Telomere length is about 15 kb in the fetus and decreases with each cell division during the organism's lifetime due to the end-replication problem.5 Thus, telomeres eventually reach a critically short length as a natural consequence of aging or due to increased proliferative stress. These short telomeres lose their ability to protect the chromosome ends and appear as DNA double-strand breaks, which induce DNA damage responses and breakage-fusion-bridge cycles that result in increased chromosomal instability and chromosomal aberrations. The cells will thus undergo apoptosis unless mutations, for example, of TP53, enable the apoptosis to be bypassed or telomeres are elongated by telomerase or alternative lengthening of telomeres. Telomere shortening has an important role in the pathogenesis of MDS and other malignancies.6

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References

  1. Mallo M, Cervera J, Schanz J, Such E, García-Manero G, Luño E et al. Impact of adjunct cytogenetic abnormalities for prognostic stratification in patients with myelodysplastic syndrome and deletion 5q. Leukemia 2011; 25: 110–120.

    Article  CAS  Google Scholar 

  2. List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355: 1456–1465.

    Article  CAS  Google Scholar 

  3. Göhring G, Giagounidis A, Büsche G, Kreipe H, Zimmermann M, Hellström-Lindberg E et al. Patients with del(5q) MDS who fail to achieve sustained erythroid or cytogenetic remission after treatment with lenalidomide have an increased risk for clonal evolution and AML progression. Ann Hematol 2008; 10: 733–739.

    Google Scholar 

  4. Jädersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Göhring G et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol 2011; 29: 1971–1979.

    Article  Google Scholar 

  5. Mayer S, Brüderlein S, Perner S, Waibel I, Holdenried A, Ciloglu N et al. Sex-specific telomere length profiles and age-dependent erosion dynamics of individual chromosome arms in humans. Cytogenet Genome Res 2006; 112: 194–201.

    Article  CAS  Google Scholar 

  6. Boultwood J, Fidler C, Kusec R, Rack K, Elliott PJ, Atoyebi O et al. Telomere length in myelodysplastic syndromes. Am J Hematol 1997; 56: 266–271.

    Article  CAS  Google Scholar 

  7. Lange K, Holm L, Vang Nielsen K, Hahn A, Hofmann W, Kreipe H et al. Telomere shortening and chromosomal instability in myelodysplastic syndromes. Genes Chromosomes Cancer 2010; 49: 260–269.

    CAS  Google Scholar 

  8. Tehranchi R, Woll PS, Anderson K, Buza-Vidas N, Mizukami T, Mead AJ et al. Persistent malignant stem cells in del(5q) myelodysplasia in remission. N Engl J Med 2010; 363: 1025–1037.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Gill Teicke for her help in editing the manuscript. This work was supported by the EuGESMA COST Action BM0801: European Genetic and Epigenetic Study on AML and MDS and by the Cluster of Excellence Rebirth.

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Author notes

  1. G Göhring and K Lange: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Pathology and Forensic and Genetic Medicine, Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

    G Göhring, K Lange, W Hofmann & B Schlegelberger

  2. Dako Denmark A/S, Glostrup, Denmark

    K V Nielsen

  3. Division of Hematology and Center of Experimental Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    E Hellström-Lindberg

  4. CHU de Poitiers, Centre de Recherche Clinique, Poitiers, France

    L Roy

  5. Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    M Morgan

  6. Centre for Pathology and Forensic and Genetic Medicine, Institute of Pathology, Hannover Medical School, Hannover, Germany

    H Kreipe & G Büsche

  7. Department of Haematology, Oncology and Clinical Immunology, St Johannes Hospital, Duisburg, Germany

    A Giagounidis

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  1. G Göhring
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  2. K Lange
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  3. W Hofmann
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Correspondence to G Göhring.

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Göhring, G., Lange, K., Hofmann, W. et al. Telomere shortening, clonal evolution and disease progression in myelodysplastic syndrome patients with 5q deletion treated with lenalidomide. Leukemia 26, 356–358 (2012). https://doi.org/10.1038/leu.2011.193

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