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Article: PRDM1 is a tumor suppressor gene in natural killer cell malignancies

TitlePRDM1 is a tumor suppressor gene in natural killer cell malignancies
Authors
Issue Date2011
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2011, v. 108 n. 50, p. 20119-20124 How to Cite?
AbstractNatural 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.
Persistent Identifierhttp://hdl.handle.net/10722/148673
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Lymphoma SPOREP50CA136411-01(NC1)
National Cancer Institute5U01/CA114778
Eppley Cancer InstituteCA36727
Council/General Research Fund of Hong KongHKU 776309M
National Institutes of Health of the National Center for Research ResourcesP20 RR016469
Funding Information:

We thank Dr. Dean A. Lee for the K562-Cl9-mb21 cell line; Dr. Norio Shimuzu for four NK-cell lines (SNK-1, SNK10, SNK-6, NK-YS) and the gamma delta T-cell lymphoma lines (SNT13, SNT15, and SNT8); Dr. I-Ming Chen for the IMC-1 cell line; Drs. Yulei Shen and Zhongfeng Liu (University of Nebraska Medical Center DNA Microarray Core Facility) for technical assistance; and Dr. Runqing Lu and Himabindu Rhamachandrareddy for helpful suggestions. YT and NK-92 were obtained from the German Collection of Microorganism and Cell Culture (GCMCC) (DSMZ, Braunschweig, Germany). KHYG1, KAI3 cell lines were obtained from the Health Science Research Resource (Osaka, Japan). This work was supported in part by Lymphoma SPORE P50CA136411-01(NC1), National Cancer Institute Grant 5U01/CA114778, Eppley Cancer Institute Core Grant CA36727, and Council/General Research Fund of Hong Kong Grant HKU 776309M. The University of Nebraska Medical Center Microarray Core Facility is supported partially by National Institutes of Health Grant P20 RR016469 from the Nebraska IDeA Network of Biomedical Research Excellence Program of the National Center for Research Resources.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorKüçük, Cen_US
dc.contributor.authorIqbal, Jen_US
dc.contributor.authorHu, Xen_US
dc.contributor.authorGaulard, Pen_US
dc.contributor.authorDe Leval, Len_US
dc.contributor.authorSrivastava, Gen_US
dc.contributor.authorAu, WYen_US
dc.contributor.authorMckeithan, TWen_US
dc.contributor.authorChan, WCen_US
dc.date.accessioned2012-05-29T06:14:35Z-
dc.date.available2012-05-29T06:14:35Z-
dc.date.issued2011en_US
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2011, v. 108 n. 50, p. 20119-20124en_US
dc.identifier.issn0027-8424en_US
dc.identifier.urihttp://hdl.handle.net/10722/148673-
dc.description.abstractNatural 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.en_US
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_US
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.subject.meshApoptosis - Drug Effectsen_US
dc.subject.meshBiopsyen_US
dc.subject.meshCell Division - Drug Effects - Geneticsen_US
dc.subject.meshCulture Media - Pharmacologyen_US
dc.subject.meshDna Copy Number Variations - Drug Effects - Geneticsen_US
dc.subject.meshDna Methylation - Drug Effects - Geneticsen_US
dc.subject.meshDna Mutational Analysisen_US
dc.subject.meshG2 Phase - Drug Effects - Geneticsen_US
dc.subject.meshGene Expression Regulation, Neoplastic - Drug Effectsen_US
dc.subject.meshGene Knockdown Techniquesen_US
dc.subject.meshGene Silencing - Drug Effectsen_US
dc.subject.meshHumansen_US
dc.subject.meshInterleukin-2 - Metabolism - Pharmacologyen_US
dc.subject.meshKiller Cells, Natural - Drug Effects - Metabolism - Pathologyen_US
dc.subject.meshLymphoma, Non-Hodgkin - Genetics - Pathologyen_US
dc.subject.meshPromoter Regions, Genetic - Geneticsen_US
dc.subject.meshRna, Small Interfering - Metabolismen_US
dc.subject.meshRepressor Proteins - Genetics - Metabolismen_US
dc.subject.meshTime Factorsen_US
dc.subject.meshTransduction, Geneticen_US
dc.subject.meshTumor Suppressor Proteins - Genetics - Metabolismen_US
dc.titlePRDM1 is a tumor suppressor gene in natural killer cell malignanciesen_US
dc.typeArticleen_US
dc.identifier.emailSrivastava, G:gopesh@pathology.hku.hken_US
dc.identifier.authoritySrivastava, G=rp00365en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1073/pnas.1115128108en_US
dc.identifier.pmid22143801en_US
dc.identifier.pmcidPMC3250125-
dc.identifier.scopuseid_2-s2.0-84055187645en_US
dc.identifier.hkuros207506-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84055187645&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume108en_US
dc.identifier.issue50en_US
dc.identifier.spage20119en_US
dc.identifier.epage20124en_US
dc.identifier.isiWOS:000298034800058-
dc.publisher.placeUnited Statesen_US
dc.relation.projectInactivation of the transcriptional repressor PRDM1 and imbalance in the expression of PRDM1 ?and ?isoforms in NK-cell malignancies, and their roles in the pathogenesis-
dc.identifier.citeulike10126480-
dc.customcontrol.immutablejt 1300315-

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