Identification of FOXO3 and PRDM1 as tumor suppressor gene candidates in NK cell neoplasms by genomic and functional analyses
Menée sur des échantillons tumoraux et des lignées cellulaires, cette étude identifie deux gènes, FOXO3 et PRDM1, susceptibles de jouer un rôle de suppresseur de tumeurs dans les néoplasies à cellules NK
Oligo-array CGH and gene expression profiling of NK cell neoplasms were employed in an effort to delineate the molecular pathogenesis involved. Oligo-array CGH identified two 6q21 regions that were most frequently deleted (36%; 14/39). One of these regions included POPDC3, PREP, PRDM1, ATG5 and AIM1, while 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 as candidate tumor suppressor genes. A20 and HACE1, the well known tumor-suppressor genes located on 6q21-23, were included as candidate genes since 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, unlike the case following re-expression of the other genes. This effect was confirmed using another NK cell line, SNK10. Furthermore, genomic analyses detected nonsense mutations of PRDM1, leading 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.
Blood 2011