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, ATG5andAIM1) 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′ ofPRDM1andAIM1correlated with low expression of the transcripts. Reversal of methylation by Decitabine induced expression ofPRDM1and cell death. In conclusion, we have shown a general tumor-promoting effect of genetic alterations and have identifiedPRDM1as the most likely target gene in del6q21.ATG5,an essential gene for autophagy andAIM1,a gene implicated in melanoma, may also participate in the functional abnormalities.