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Lymphoma

Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies

Leukemia volume 23, pages 1139–1151 (2009)Cite this article

Abstract

Natural killer (NK)-cell malignancies are among the most aggressive lymphoid neoplasms with very poor prognosis. We performed array comparative genomic hybridization analysis on a number of NK cell lines and primary tumors to gain better understanding of the pathogenesis and tumor biology of these malignancies. We also obtained transcriptional profiles of genes residing in these regions and compared them with normal and activated NK cells. Only 30–50% of the genes residing in the gained or deleted regions showed corresponding increased or decreased expression. However, many of the upregulated genes in regions of gain are functionally important for the proliferation and growth of the neoplastic population. Genes downregulated in regions of loss included many transcription factors or repressors, tumor suppressors or negative regulators of the cell cycle. The minimal common region of deletion in 6q21 included three known genes (PRDM1, ATG5 and AIM1) showing generally low expression. Mutations resulting in truncated PRDM1 and changes in conserved amino-acid sequences of AIM1 were detected. Highly methylated CpG islands 5′ of PRDM1 and AIM1 correlated with low expression of the transcripts. Reversal of methylation by Decitabine induced expression of PRDM1 and cell death. In conclusion, we have shown a general tumor-promoting effect of genetic alterations and have identified PRDM1 as the most likely target gene in del6q21. ATG5, an essential gene for autophagy and AIM1, a gene implicated in melanoma, may also participate in the functional abnormalities.

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Acknowledgements

This study was supported in part by a NCI Grant (5U01/CA114778) and funds from Genome center Canada/British Columbia. We thank Dr Junjiro Tsuchiyama and Dr Yoshitoyo Kagami for NK-YS and HANK-1 cell lines, respectively. The UNMC Microarray Core Facility Dr James Eudy supported partially by NIH Grant P20 RR016469 from the INBRE Program of the National Center for Research Resources.

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Author notes

  1. J Iqbal and C Kucuk: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    J Iqbal, C Kucuk, K Patel & W C Chan

  2. British Columbia Cancer Research Centre, Vancouver, British columbia, Canada

    R J deLeeuw, I F L Tsui & W L Lam

  3. Departments of Pathology and Medicine, University of Hong Kong, Hong Kong, Hong Kong

    G Srivastava, L Shen & W Y Au

  4. Department of Pathology, Weill Medical College of Cornell University, New York, NY, USA

    W Tam

  5. Department of Computer Science, University of Nebraska at Omaha, Omaha, NE, USA

    H Geng, K Cao & H Ali

  6. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    D Klinkebiel & J K Christman

  7. Department of Hematology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark

    K Dybkaer

  8. Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

    N Shimizu

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Correspondence to W C Chan.

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

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Iqbal, J., Kucuk, C., deLeeuw, R. et al. Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies. Leukemia 23, 1139–1151 (2009). https://doi.org/10.1038/leu.2009.3

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