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Segmental chromosomal aberrations and centrosome amplifications: pathogenetic mechanisms in Hodgkin and Reed–Sternberg cells of classical Hodgkin's lymphoma?

Leukemia volume 17, pages 2214–2219 (2003)Cite this article

Abstract

Tumor cell metaphases of classical Hodgkin's lymphoma (cHL) characteristically display highly rearranged karyotypes with chromosome numbers in the hyperploid range and marked intraclonal variability. The causes of this cytogenetic pattern remain largely unknown. An unusual type of chromosomal abnormality coined as segmental chromosomal aberration (SCA) has been recurrently observed in HL cell lines and was suggested to be associated with ribosomal DNA (rDNA) rearrangements. Moreover, centrosome abnormalities provoking deficient chromosome segregation have been reported in many solid tumors and also in cHL cell lines. Whether SCA, rDNA rearrangements or centrosome abnormalities also occur in primary cHL is not yet known. Thus, we performed extensive molecular cytogenetic and immunohistological studies in two cHL cases. Both cases presented SCA associated with genomic gains of the REL and JAK2 loci, respectively. The SCA involving JAK2 was associated with rDNA rearrangements. The absolute centrosome size of HRS cells in both cases was significantly larger than in non-HRS cells, but the relative centrosome size of HRS cells corrected for nuclear size was in the same range as that of the non-neoplastic cells. These findings demonstrate that the various mechanisms associated with chromosomal instability warrant a more detailed characterization in cHL.

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References

  1. Drexler HG . Recent results on the biology of Hodgkin and Reed–Sternberg cells. I. Biopsy material. Leuk Lymphoma 1992; 8: 283–313.

    Article  CAS  Google Scholar 

  2. Deerberg-Wittram J, Weber-Matthiesen K, Schlegelberger B . Cytogenetics and molecular cytogenetics in Hodgkin's disease. Ann Oncol 1996; 7 (Suppl 4): 49–53.

    Article  Google Scholar 

  3. Atkin NB . Cytogenetics of Hodgkin's disease. Cytogenet Cell Genet 1998; 80: 23–27.

    Article  CAS  Google Scholar 

  4. Falzetti D, Crescenzi B, Matteuci C, Falini B, Martelli MF, Van Den Berghe H et al. Genomic instability and recurrent breakpoints are main cytogenetic findings in Hodgkin's disease. Haematologica 1999; 84: 298–305.

    CAS  PubMed  Google Scholar 

  5. Siebert R, Rosenwald A, Staudt LM, Morris SW . Molecular features of B-cell lymphoma. Curr Opin Oncol 2001; 13: 316–324.

    Article  CAS  Google Scholar 

  6. Weber-Matthiesen K, Deerberg J, Poetsch M, Grote W, Schlegelberger B . Numerical chromosome aberrations are present within the CD30+ Hodgkin and Reed–Sternberg cells in 100% of analyzed cases of Hodgkin's disease. Blood 1995; 86: 1464–1468.

    CAS  PubMed  Google Scholar 

  7. Ohshima K, Ishiguro M, Ohgami A, Sugihara M, Haraoka S, Suzumiya J et al. Genetic analysis of sorted Hodgkin and Reed–Sternberg cells using comparative genomic hybridization. Int J Cancer 1999; 82: 250–255.

    Article  CAS  Google Scholar 

  8. Joos S, Küpper M, Ohl S, von Bonin F, Mechtersheimer G, Bentz M et al. Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells. Cancer Res 2000; 60: 549–552.

    CAS  PubMed  Google Scholar 

  9. MacLeod RA, Spitzer D, Bar-Am I, Sylvester JE, Kaufmann M, Wernich A et al. Karyotypic dissection of Hodgkin's disease cell lines reveals ectopic subtelomeres and ribosomal DNA at sites of multiple jumping translocations and genomic amplification. Leukemia 2000; 14: 1803–1814.

    Article  CAS  Google Scholar 

  10. Küpper M, Joos S, von Bonin F, Daus H, Pfreundschuh M, Lichter P et al. MDM2 gene amplification and lack of p53 point mutations in Hodgkin and Reed–Sternberg cells: results from single-cell polymerase chain reaction and molecular cytogenetic studies. Br J Haematol 2001; 112: 768–775.

    Article  Google Scholar 

  11. Joos S, Menz CK, Wrobel G, Siebert R, Gesk S, Ohl S et al. Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2. Blood 2002; 99: 1381–1387.

    Article  CAS  Google Scholar 

  12. Martin-Subero JI, Gesk S, Harder L, Sonoki T, Tucker PW, Schlegelberger B et al. Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma. Blood 2002; 99: 1474–1477.

    Article  CAS  Google Scholar 

  13. Joos S, Granzow M, Holtgreve-Grez H, Siebert R, Harder L, Martin-Subero JI et al. Hodgkin's lymphoma cell lines are characterized by frequent aberrations on chromosomes 2p and 9p including REL and JAK2. Int J Cancer 2003; 103: 489–495.

    Article  CAS  Google Scholar 

  14. Berglund M, Flordal E, Gullander J, Lui WO, Larsson C, Lagercrantz S et al. Molecular cytogenetic characterization of four commonly used cell lines derived from Hodgkin lymphoma. Cancer Genet Cytogenet 2003; 141: 43–48.

    Article  CAS  Google Scholar 

  15. Barth TF, Martin-Subero JI, Joos S, Menz CK, Hasel C, Mechtersheimer G et al. Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin's lymphoma. Blood 2003; 101: 3681–3686.

    Article  CAS  Google Scholar 

  16. Tanaka K, Arif M, Eguchi M, Kyo T, Dohy H, Kamada N . Frequent jumping translocations of chromosomal segments involving the ABL oncogene alone or in combination with CD3-MLL genes in secondary leukemias. Blood 1997; 89: 596–600.

    CAS  Google Scholar 

  17. Tanaka K, Kamada N . Segmental jumping translocation in leukemia and lymphoma with a highly complex karyotype. Leuk Lymphoma 1998; 29: 563–575.

    Article  CAS  Google Scholar 

  18. Lejeune J, Maunoury C, Prieur M, Van den Akker J . Translocation sauteuse (5p;15q), (8q;15q), and (12q;15q). Ann Genet 1979; 22: 210–213.

    CAS  PubMed  Google Scholar 

  19. Cuthbert G, McCullough S, Finney R, Breese G, Bown N . Jumping translocation at 11q23 with MLL gene rearrangement and interstitial telomeric sequences. Genes Chromosomes Cancer 1999; 24: 295–298.

    Article  CAS  Google Scholar 

  20. Pihan GA, Purohit A, Wallace J, Knecht H, Woda B, Quesenberry P et al. Centrosome defects and genetic instability in malignant tumors. Cancer Res 1998; 58: 3974–3985.

    CAS  Google Scholar 

  21. Nigg EA . Centrosome aberrations: cause or consequence of cancer progression? Nat Rev Cancer 2002; 2: 815–825.

    Article  CAS  Google Scholar 

  22. Krämer A, Neben K, Ho AD . Centrosome replication, genomic instability and cancer. Leukemia 2002; 16: 767–775.

    Article  Google Scholar 

  23. Fukasawa K . Introduction: centrosome. Oncogene 2002; 21: 6140–6145.

    Article  CAS  Google Scholar 

  24. Neben K, Giesecke C, Schweizer S, Ho AD, Krämer A . Centrosome aberrations in acute myeloid leukemia are correlated with cytogenetic risk profile. Blood 2003; 101: 289–291.

    Article  CAS  Google Scholar 

  25. Schlegelberger B, Metzke S, Harder S, Zühlke-Jenisch R, Zhang Y, Siebert R . Classical, molecular cytogenetics of tumor cells. In: Wegner R (ed). Diagnostic Cytogenetics. New York: Springer-Verlag, 1999 pp 151–185.

    Chapter  Google Scholar 

  26. Martin-Subero JI, Chudoba I, Harder L, Gesk S, Grote W, Novo FJ et al. Multicolor-FICTION: expanding the possibilities of combined morphologic, immunophenotypic, and genetic single cell analyses. Am J Pathol 2002; 161: 413–420.

    Article  CAS  Google Scholar 

  27. Page SL, Shin JC, Han JY, Choo KH, Shaffer LG . Breakpoint diversity illustrates distinct mechanisms for Robertsonian translocation formation. Hum Mol Genet 1996; 5: 1279–1288.

    Article  CAS  Google Scholar 

  28. Kolomietz E, Meyn MS, Pandita A, Squire JA . The role of Alu repeat clusters as mediators of recurrent chromosomal aberrations in tumors. Genes Chromosomes Cancer 2002; 35: 97–112.

    Article  CAS  Google Scholar 

  29. Pihan GA, Purohit A, Wallace J, Malhotra R, Liotta L, Doxsey SJ . Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression. Cancer Res 2001; 61: 2212–2219.

    CAS  Google Scholar 

  30. Herrmann L, Dittmar T, Erdmann KS . The protein tyrosine phosphatase PTP-BL associates with the midbody and is involved in the regulation of cytokinesis. Mol Biol Cell 2003; 14: 230–240.

    Article  CAS  Google Scholar 

  31. Rios RM, Bornens M . The Golgi apparatus at the cell centre. Curr Opin Cell Biol 2003; 15: 60–66.

    Article  CAS  Google Scholar 

  32. Zhou H, Kuang J, Zhong L, Kuo WL, Gray JW, Sahin A et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 1998; 20: 189–193.

    Article  CAS  Google Scholar 

  33. Meraldi P, Honda R, Nigg EA . Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53−/− cells. EMBO J 2002; 21: 483–492.

    Article  CAS  Google Scholar 

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Acknowledgements

This article is dedicated to Professor Dr Werner Grote, Director of the Institute of Human Genetics of the University Hospital Schleswig-Holstein (Campus Kiel), on the occasion of his 65th birthday. We thank Dorit Schuster and Claudia Becher for their excellent technical assistance and Dr Jochen Heukeshoven for peptide synthesis. Clones for rDNA sequences and the centromere of chromosome 20 were kindly provided by Dr Mariano Rocchi from the University of Bari (Italy, http://www.biologia.uniba.it/rmc).

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Authors and Affiliations

  1. Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel, Germany

    J I Martín-Subero, L Harder, J Riemke, S Grohmann, S Gesk, J Höppner & R Siebert

  2. Abteilung für Viszeral- und Transplantationschirurgie, Universitätsklinikum Ulm, Germany

    U Knippschild

  3. Abteilung für Pathologie, Universitätsklinikum Ulm, Germany

    T F E Barth & P Möller

  4. Institute of Hematopathology, University Hospital Schleswig-Holstein, Campus Kiel, Germany

    R M Parwaresch

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  1. J I Martín-Subero
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Martín-Subero, J., Knippschild, U., Harder, L. et al. Segmental chromosomal aberrations and centrosome amplifications: pathogenetic mechanisms in Hodgkin and Reed–Sternberg cells of classical Hodgkin's lymphoma?. Leukemia 17, 2214–2219 (2003). https://doi.org/10.1038/sj.leu.2403129

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