title: PRDM1 is a tumor suppressor gene in natural killer cell malignancies.
abstract: Natural killer cell lymphoma (NKCL) constitutes a rare and aggressive form of non-Hodgkin lymphoma, and there is little insight into its pathogenesis. Here we show that PRDM1 is a tumor suppressor gene in NKCLs that is inactivated by a combination of monoallelic deletion and promoter CpG island hypermethylation. We observed monoallelic deletion of PRDM1 loci in 8 of 18 (44%) NKCL cases. The other allele showed significant promoter methylation in 12 of 17 (71%) cases. In support of its role as a tumor suppressor gene, the reconstitution of PRDM1 in PRDM1-null NK cell lines led to G2/M cell cycle arrest, increased apoptosis, and a strong negative selection pressure with progressive elimination of PRDM1-expressing cells, which was enhanced when IL-2 concentration is limiting. We observed a progressive increase in PRDM1 expression--in particular, PRDM1α--in normal NK cells in response to IL-2 and in normal NK cells activated with an engineered NK cell target, K562-Cl9-mb21, suggesting its role in NK cell homeostasis. In support of this role, knockdown of PRDM1 by shRNA in normal NK cells resulted in the positive selection of these cells. We identified MYC and 4-1BBL as targets of PRDM1 in NK cells. Disruption of homeostatic control by PRDM1 may be an important pathogenetic mechanism for NKCL.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Can
authors.initials: C
authors.lastname: Küçük
authors.forename: Javeed
authors.initials: J
authors.lastname: Iqbal
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Hu
authors.forename: Phillip
authors.initials: P
authors.lastname: Gaulard
authors.forename: Laurence
authors.initials: L
authors.lastname: De Leval
authors.forename: Gopesh
authors.initials: G
authors.lastname: Srivastava
authors.forename: Wing Yan
authors.initials: WY
authors.lastname: Au
authors.forename: Timothy W
authors.initials: TW
authors.lastname: McKeithan
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001706:Biopsy; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D003470:Culture Media / Q000494:pharmacology; D056915:DNA Copy Number Variations / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D004252:DNA Mutational Analysis; D016195:G2 Phase / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000473:pathology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D003470:Culture Media; D007376:Interleukin-2; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1