PRDM1 is a tumor suppressor gene in natural killer cell malignancies
| Autor: | Wing C. Chan, Timothy W. McKeithan, Javeed Iqbal, Phillip Gaulard, Laurence de Leval, Wing Y. Au, Can Küçük, Gopesh Srivastava, Xiaozhou Hu |
|---|---|
| Přispěvatelé: | Guellaen, Georges, Department of Pathology and Microbiology, University of Nebraska Medical Center, University of Nebraska System-University of Nebraska System, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Pathologie Clinique, Université de Lausanne = University of Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)-Institut Universitaire de Pathologie, Departments of Pathology and Medicine, The University of Hong Kong (HKU)-Queen mary Hospital, Department of Internal Medicine, 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., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Université de Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)-Institut Universitaire de Pathologie |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Time Factors
Biopsy Apoptosis Rna Small Interfering - Metabolism Interleukin-2 - Metabolism - Pharmacology biotage pyrosequencing Interleukin 21 0302 clinical medicine Transduction Genetic hemic and lymphatic diseases Tumor Suppressor Proteins - Genetics - Metabolism RNA Small Interfering Promoter Regions Genetic Gene Expression Regulation Neoplastic - Drug Effects 0303 health sciences Multidisciplinary Repressor Proteins - Genetics - Metabolism Lymphoma Non-Hodgkin Biological Sciences Gene Expression Regulation Neoplastic Killer Cells Natural Dna Mutational Analysis Gene Silencing - Drug Effects Dna Copy Number Variations - Drug Effects - Genetics medicine.anatomical_structure 030220 oncology & carcinogenesis Gene Knockdown Techniques DNA methylation G2 Phase - Drug Effects - Genetics Interleukin 12 NK-cell activation and homeostasis Cell Division Cell Division - Drug Effects - Genetics G2 Phase Apoptosis - Drug Effects DNA Copy Number Variations Tumor suppressor gene Biology Natural killer cell Killer Cells Natural - Drug Effects - Metabolism - Pathology 03 medical and health sciences Dna Methylation - Drug Effects - Genetics PRDM1 medicine [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Gene Silencing 030304 developmental biology Lymphokine-activated killer cell Tumor Suppressor Proteins Culture Media - Pharmacology DNA Methylation Molecular biology CCNG2 Culture Media Repressor Proteins neoplastic transformation CCNG1 Cancer research Myeloid-derived Suppressor Cell Lymphoma Non-Hodgkin - Genetics - Pathology Interleukin-2 Positive Regulatory Domain I-Binding Factor 1 Promoter Regions Genetic - Genetics |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2011, 108 (50), pp.20119-24. ⟨10.1073/pnas.1115128108⟩ Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 50, pp. 20119-20124 |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.1073/pnas.1115128108 |
| Popis: | 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. link_to_OA_fulltext |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|