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Cytogenetics and Molecular Genetics

Recurrent genomic aberrations combined with deletions of various tumour suppressor genes may deregulate the G1/S transition in CD4+CD56+ haematodermic neoplasms and contribute to the aggressiveness of the disease

Leukemia volume 23, pages 698–707 (2009)Cite this article

A Corrigendum to this article was published on 15 April 2009

Abstract

CD4+CD56+ haematodermic neoplasms (HDN) constitute a rare disease characterized by aggressive clinical behaviour and a poor prognosis. Tumour cells from HDN are leukaemic counterparts of plasmacytoid dendritic cells (pDCs). Despite increased knowledge of the ontogenetic origin of these tumours, the genetic causes and oncogenic signalling events involved in malignant transformation are still unknown. To delineate novel candidate regions and disease-related genes, we studied nine typical CD4+CD56+ HDN cases using genome-wide high-resolution array comparative genomic hybridization (CGH). Genomic imbalances, which were predominantly losses, were frequently detected. Gross genomic losses or gains involving an entire chromosome were observed in eight cases. The most frequent imbalances were deletions of chromosome 9, chromosome 13 and partial losses affecting 17p or 12p. Combinations of deletions of tumour suppressor genes (TSG), namely RB1, CDKN1B (p27), CDKN2A, (p16ink4a, p14arf) or TP53 (p53), were observed in all cases. These results indicate that deletion events altering G1/S regulation are crucial for HDN oncogenesis. Furthermore, in addition to frequent sporadic gene losses, in one case we observed a 8q24 interstitial deletion that brought MYC closer to miR-30b/miR-30d, which may be related to their deregulation. Taken together, these results indicate that in addition to frequent G1/S checkpoint alterations, various genetic events could contribute to the chemoresistance of the tumour.

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References

  1. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768–3785.

    CAS  PubMed  Google Scholar 

  2. Feuillard J, Jacob MC, Valensi F, Maynadie M, Gressin R, Chaperot L et al. Clinical and biologic features of CD4(+)CD56(+) malignancies. Blood 2002; 99: 1556–1563.

    Article  CAS  PubMed  Google Scholar 

  3. Garnache-Ottou F, Feuillard J, Saas P . Plasmacytoid dendritic cell leukaemia/lymphoma: towards a well defined entity? Br J Haematol 2007; 136: 539–548.

    Article  CAS  PubMed  Google Scholar 

  4. Petrella T, Bagot M, Willemze R, Beylot-Barry M, Vergier B, Delaunay M et al. Blastic NK-cell lymphomas (agranular CD4+CD56+ hematodermic neoplasms): a review. Am J Clin Pathol 2005; 123: 662–675.

    Article  PubMed  Google Scholar 

  5. Pilichowska ME, Fleming MD, Pinkus JL, Pinkus GS . CD4+/CD56+ hematodermic neoplasm (‘blastic natural killer cell lymphoma’): neoplastic cells express the immature dendritic cell marker BDCA-2 and produce interferon. Am J Clin Pathol 2007; 128: 445–453.

    Article  CAS  PubMed  Google Scholar 

  6. Herling M, Jones D . CD4+/CD56+ hematodermic tumor: the features of an evolving entity and its relationship to dendritic cells. Am J Clin Pathol 2007; 127: 687–700.

    Article  PubMed  Google Scholar 

  7. Leroux D, Mugneret F, Callanan M, Radford-Weiss I, Dastugue N, Feuillard J et al. CD4(+), CD56(+) DC2 acute leukemia is characterized by recurrent clonal chromosomal changes affecting 6 major targets: a study of 21 cases by the Groupe Francais de Cytogenetique Hematologique. Blood 2002; 99: 4154–4159.

    Article  CAS  PubMed  Google Scholar 

  8. Dijkman R, van Doorn R, Szuhai K, Willemze R, Vermeer MH, Tensen CP . Gene-expression profiling and array-based CGH classify CD4+CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities. Blood 2007; 109: 1720–1727.

    Article  CAS  PubMed  Google Scholar 

  9. Chaperot L, Bendriss N, Manches O, Gressin R, Maynadie M, Trimoreau F et al. Identification of a leukemic counterpart of the plasmacytoid dendritic cells. Blood 2001; 97: 3210–3217.

    Article  CAS  PubMed  Google Scholar 

  10. Chaperot L, Blum A, Manches O, Lui G, Angel J, Molens JP et al. Virus or TLR agonists induce TRAIL-mediated cytotoxic activity of plasmacytoid dendritic cells. J Immunol 2006; 176: 248–255.

    Article  CAS  PubMed  Google Scholar 

  11. Bastard C, Raux G, Fruchart C, Parmentier F, Vaur D, Penther D et al. Comparison of a quantitative PCR method with FISH for the assessment of the four aneuploidies commonly evaluated in CLL patients. Leukemia 2007; 21: 1460–1463.

    Article  CAS  PubMed  Google Scholar 

  12. Quintanilla-Martinez L, Kremer M, Keller G, Nathrath M, Gamboa-Dominguez A, Meneses A et al. p53 Mutations in nasal natural killer/T-cell lymphoma from Mexico: association with large cell morphology and advanced disease. Am J Pathol 2001; 159: 2095–2105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Huppi K, Volfovsky N, Runfola T, Jones TL, Mackiewicz M, Martin SE et al. The identification of microRNAs in a genomically unstable region of human chromosome 8q24. Mol Cancer Res 2008; 6: 212–221.

    Article  CAS  PubMed  Google Scholar 

  14. Rucker FG, Bullinger L, Schwaenen C, Lipka DB, Wessendorf S, Frohling S et al. Disclosure of candidate genes in acute myeloid leukemia with complex karyotypes using microarray-based molecular characterization. J Clin Oncol 2006; 24: 3887–3894.

    Article  PubMed  Google Scholar 

  15. Hangaishi A, Ogawa S, Imamura N, Miyawaki S, Miura Y, Uike N et al. Inactivation of multiple tumor-suppressor genes involved in negative regulation of the cell cycle, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B, p53, and Rb genes in primary lymphoid malignancies. Blood 1996; 87: 4949–4958.

    CAS  PubMed  Google Scholar 

  16. Trovo-Marqui AB, Tajara EH . Neurofibromin: a general outlook. Clin Genet 2006; 70: 1–13.

    Article  CAS  PubMed  Google Scholar 

  17. Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R et al. Characterizing the cancer genome in lung adenocarcinoma. Nature 2007; 450: 893–898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dallol A, Da Silva NF, Viacava P, Minna JD, Bieche I, Maher ER et al. SLIT2, a human homologue of the Drosophila Slit2 gene, has tumor suppressor activity and is frequently inactivated in lung and breast cancers. Cancer Res 2002; 62: 5874–5880.

    CAS  PubMed  Google Scholar 

  19. Furuta J, Nobeyama Y, Umebayashi Y, Otsuka F, Kikuchi K, Ushijima T . Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas. Cancer Res 2006; 66: 6080–6086.

    Article  CAS  PubMed  Google Scholar 

  20. Her C, Zhao N, Wu X, Tompkins JD . MutS homologues hMSH4 and hMSH5: diverse functional implications in humans. Front Biosci 2007; 12: 905–911.

    Article  CAS  PubMed  Google Scholar 

  21. Tavera-Mendoza LE, Wang TT, White JH . p19INK4D and cell death. Cell Cycle 2006; 5: 596–598.

    Article  CAS  PubMed  Google Scholar 

  22. Niida H, Nakanishi M . DNA damage checkpoints in mammals. Mutagenesis 2006; 21: 3–9.

    Article  CAS  PubMed  Google Scholar 

  23. Davies SR, Watkins G, Mansel RE, Jiang WG . Differential expression and prognostic implications of the CCN family members WISP-1, WISP-2, and WISP-3 in human breast cancer. Ann Surg Oncol 2007; 14: 1909–1918.

    Article  PubMed  Google Scholar 

  24. Hamaguchi M, Meth JL, von Klitzing C, Wei W, Esposito D, Rodgers L et al. DBC2, a candidate for a tumor suppressor gene involved in breast cancer. Proc Natl Acad Sci USA 2002; 99: 13647–13652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Radulescu RT . One for all and all for one: RB defends the cell while IDE, PTEN and IGFBP-7 antagonize insulin and IGFs to protect RB. Med Hypotheses 2007; 69: 1018–1020.

    Article  CAS  PubMed  Google Scholar 

  26. Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM et al. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet 2008; 40: 43–50.

    Article  CAS  PubMed  Google Scholar 

  27. Martinez I, Gardiner AS, Board KF, Monzon FA, Edwards RP, Khan SA . Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells. Oncogene 2008; 27: 2575–2582.

    Article  CAS  PubMed  Google Scholar 

  28. Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P et al. MicroRNA signatures in human ovarian cancer. Cancer Res 2007; 67: 8699–8707.

    Article  CAS  PubMed  Google Scholar 

  29. Gauwerky CE, Huebner K, Isobe M, Nowell PC, Croce CM . Activation of MYC in a masked t(8;17) translocation results in an aggressive B-cell leukemia. Proc Natl Acad Sci USA 1989; 86: 8867–8871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. INSERM, U918, European Institute of Peptide Research (IFR23), Centre Henri Becquerel, Rouen, France

    F Jardin, D Penther, P Ruminy, F Parmentier, V Rainville, P Bertrand, J M Picquenot, H Tilly & C Bastard

  2. Department of Hematology, Centre Henri Becquerel, Rouen, France

    F Jardin & H Tilly

  3. Molecular and Cellular Haematology Unit, Grenoble, France

    M Callanan

  4. Team 7, Centre de recherche INSERM-Joseph Fourier University, U823, Grenoble, France

    M Callanan

  5. UPRES EA 3919, Cote de Nacre University Hospital, Caen, France

    X Troussard

  6. INSERM U837, Université de Lille2 - IFR 114 and Institut de Recherche sur le Cancer, Lille, France

    J P Kerckaert & M Figeac

  7. Department of Haematology, University Hospital, Amiens, France

    I Vaida & J P Marolleau

  8. Department of Dermatology, Charles Nicolle University Hospital, Rouen, France

    A B Duval

  9. Department of Oncogenesis and Biotechnology, and Department de Research and Development, Team 9, Joseph Fourier University, U823, Etablissement Français du Sang Rhone-Alpes—Site de La Tronche, Grenoble, France

    L Chaperot & J Plumas

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  1. F Jardin
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Correspondence to F Jardin.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Jardin, F., Callanan, M., Penther, D. et al. Recurrent genomic aberrations combined with deletions of various tumour suppressor genes may deregulate the G1/S transition in CD4+CD56+ haematodermic neoplasms and contribute to the aggressiveness of the disease. Leukemia 23, 698–707 (2009). https://doi.org/10.1038/leu.2008.359

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