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.

  • Brief Communication
  • Published:

Acute myeloid leukemia

SMC3 protein levels impact on karyotype and outcome in acute myeloid leukemia

Leukemia volume 33, pages 795–799 (2019)Cite this article

Subjects

Chromosomal instability (CIN) is a major contributor to genetic heterogeneity and clonal diversification in both human solid tumors and hematological malignancies. Its levels increase with advancing age both in normal and malignant cells [1,2,3]. In elderly healthy individuals clonal mosaicism for chromosomal aberrations in blood cells is associated with an increased risk for the development of a subsequent myeloid malignancy [3]. Chromosomal aberrations arise as a consequence of errors during mitosis. For accurate chromosome segregation, sister chromatids are tightly associated until the spindle assembly checkpoint is satisfied, allowing for anaphase-promoting complex (APC/C)-mediated anaphase onset. Until anaphase, sister chromatid cohesion is established by the ring-shaped cohesin complex consisting of four subunits (SMC1A, SMC3, Rad21, and either SA-1 or SA-2).

Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disorder with highest incidence in the elderly [2]. Advancing age and complex karyotype aberrations, two strong adverse prognostic factors in AML, are closely interconnected and responsible for poor treatment outcome. Despite major advances in understanding the genetic landscape of AML and its impact on disease pathophysiology, why genomic integrity declines with age is barely uncovered. As compared to somatic cell divisions, chromosome segregation errors occur more frequently during meiosis, with age-associated CIN in oocytes being a consequence of cohesin decay with increasing maternal age [4].

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

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

Fig. 1
Fig. 2

References

  1. Bochtler T, Frohling S, Krämer A. Role of chromosomal aberrations in clonal diversity and progression of acute myeloid leukemia. Leukemia. 2015;29:1243–52.

    Article  CAS  Google Scholar 

  2. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    Article  Google Scholar 

  3. Laurie CC, Laurie CA, Rice K, Doheny KF, Zelnick LR, McHugh CP, et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet. 2012;44:642–50.

    Article  CAS  Google Scholar 

  4. Jessberger R. Age-related aneuploidy through cohesion exhaustion. EMBO Rep. 2012;13:539–46.

    Article  CAS  Google Scholar 

  5. Kon A, Shih LY, Minamino M, Sanada M, Shiraishi Y, Nagata Y, et al. Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. Nat Genet. 2013;45:1232–7.

    Article  CAS  Google Scholar 

  6. Thota S, Viny AD, Makishima H, Spitzer B, Radivoyevitch T, Przychodzen B, et al. Genetic alterations of the cohesin complex genes in myeloid malignancies. Blood. 2014;124:1790–8.

    Article  CAS  Google Scholar 

  7. Fisher JB, McNulty M, Burke MJ, Crispino JD, Rao S. Cohesin Mutations in Myeloid Malignancies. Trends Cancer. 2017;3:282–93.

    Article  CAS  Google Scholar 

  8. Remeseiro S, Cuadrado A, Carretero M, Martinez P, Drosopoulos WC, Canamero M, et al. Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres. EMBO J. 2012;31:2076–89.

    Article  CAS  Google Scholar 

  9. Cuadrado A, Remeseiro S, Gomez-Lopez G, Pisano DG, Losada A. The specific contributions of cohesin-SA1 to cohesion and gene expression: implications for cancer and development. Cell Cycle. 2012;11:2233–8.

    Article  CAS  Google Scholar 

  10. Viny AD, Ott CJ, Spitzer B, Rivas M, Meydan C, Papalexi E, et al. Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis. J Exp Med. 2015;212:1819–32.

    Article  CAS  Google Scholar 

  11. Thol F, Bollin R, Gehlhaar M, Walter C, Dugas M, Suchanek KJ, et al. Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications. Blood. 2014;123:914–20.

    Article  CAS  Google Scholar 

  12. Losada A. Cohesin in cancer: chromosome segregation and beyond. Nat Rev Cancer. 2014;14:389–93.

    Article  CAS  Google Scholar 

  13. Barber TD, McManus K, Yuen KW, Reis M, Parmigiani G, Shen D, et al. Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers. Proc Natl Acad Sci USA. 2008;105:3443–8.

    Article  CAS  Google Scholar 

  14. Carvalhal S, Tavares A, Santos MB, Mirkovic M, Oliveira RA. A quantitative analysis of cohesin decay in mitotic fidelity. J Cell Biol. 2018; https://doi.org/10.1083/jcb.201801111 [Epub ahead of print].

    Article  CAS  Google Scholar 

  15. Heidinger-Pauli JM, Mert O, Davenport C, Guacci V, Koshland D. Systematic reduction of cohesin differentially affects chromosome segregation, condensation, and DNA repair. Curr Biol. 2010;20:957–63.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Deutsche Forschungsgemeinschaft (DFG) and Wilhelm Sander-Stiftung.

Author information

Authors and Affiliations

  1. Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    Bianca Kraft, Jan Lombard, Michael Kirsch & Alwin Krämer

  2. Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, German Red Cross Blood Service Baden-Wuerttemberg—Hessen, Mannheim, Germany

    Patrick Wuchter & Peter Bugert

  3. Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Thomas Hielscher

  4. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    Norbert Blank & Alwin Krämer

Authors
  1. Bianca Kraft
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jan Lombard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Kirsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patrick Wuchter
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Bugert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas Hielscher
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Norbert Blank
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alwin Krämer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alwin Krämer.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kraft, B., Lombard, J., Kirsch, M. et al. SMC3 protein levels impact on karyotype and outcome in acute myeloid leukemia. Leukemia 33, 795–799 (2019). https://doi.org/10.1038/s41375-018-0287-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-018-0287-6

This article is cited by

Search

Advanced search

Quick links