title: Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses.
abstract: Oligo-array comparative genomic hybridization (CGH) and gene-expression profiling of natural killer (NK)-cell neoplasms were used in an effort to delineate the molecular pathogenesis involved. Oligo-array CGH identified two 6q21 regions that were most frequently deleted (14 of 39 or 36%). One of these regions included POPDC3, PREP, PRDM1, ATG5, and AIM1, whereas the other included LACE1 and FOXO3. All genes located in these regions, except for POPDC3 and AIM1, were down-regulated in neoplastic samples, as determined by gene-expression analysis, and were therefore considered to be candidate tumor-suppressor genes. A20 and HACE1, the well-known tumor-suppressor genes located on 6q21-23, were included as candidate genes because they also demonstrated frequent genomic deletions and down-regulated expression. The Tet-Off NK cell line NKL was subsequently established for functional analyses. Seven candidate genes were transduced into Tet-Off NKL and forced re-expression was induced. Re-expression of FOXO3 and PRDM1 suppressed NKL proliferation, but this was not the case after re-expression of the other genes. This effect was confirmed using another NK cell line, SNK10. Furthermore, genomic analyses detected nonsense mutations of PRDM1 that led to functional inactivation in one cell line and one clinical sample. PRDM1 and FOXO3 are considered to play an important role in the pathogenesis of NK-cell neoplasms.
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Kennosuke
authors.initials: K
authors.lastname: Karube
authors.forename: Masao
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Shinobu
authors.initials: S
authors.lastname: Tsuzuki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takeuchi
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Honma
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakashima
authors.forename: Norio
authors.initials: N
authors.lastname: Shimizu
authors.forename: Young-Hyeh
authors.initials: YH
authors.lastname: Ko
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Morishima
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakamura
authors.forename: Masao
authors.initials: M
authors.lastname: Seto
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002648:Child; D055028:Comparative Genomic Hybridization / Q000379:methods*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D015894:Genome, Human; D023281:Genomics / Q000379:methods*; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism* / Q000473:pathology; D054066:Leukemia, Large Granular Lymphocytic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae; D014161:Transduction, Genetic
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1