1. ¹Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
2. ²British Columbia Cancer Research Centre, Vancouver, British columbia, Canada
3. ³Departments of Pathology and Medicine, University of Hong Kong, Hong Kong, Hong Kong
4. ⁴Department of Pathology, Weill Medical College of Cornell University, New York, NY, USA
5. ⁵Department of Computer Science, University of Nebraska at Omaha, Omaha, NE, USA
6. ⁶Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
7. ⁷Department of Hematology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark
8. ⁸Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

Correspondence: WC Chan, Amelia and Austin Vickery Professor of Pathology, University of Nebraska Medical Center, 983135 Nebraska Medical Center, Omaha, NE 68198, USA. E-mail: jchan@unmc.edu

⁹These authors contributed equally to this work.

Received 23 September 2008; Revised 25 November 2008; Accepted 22 December 2008; Published online 5 February 2009.

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.